Arylethenesulfonamide derivatives and drug composition containing the same

ABSTRACT

Novel arylethenesulfonamide derivative having a high affinity for drugs, especially endoserine receptors, and represented by general formula (I); pharmaceutically acceptable salts thereof; and drugs comprising the same as the active ingredient, especially endoserine receptor antagonist, wherein 
     Ar: optionally substituted aryl group or optionally substituted five- to six-membered heteroaryl group; 
     X: oxygen atom, sulfur atom or a group represented by a formula --NH--; 
     Y: oxygen atom or sulfur atom; 
     R 1  : hydrogen atom, optionally halogen-substituted lower alkyl group, cycloalkyl group, optionally substituted aryl group or optionally substituted five- to six-membered heteroaryl group. 
     R 2  : lower alkyl group, lower alkenyl group or lower alkynyl group where each of which may be substituted with one to three substituent(s) selected from a group consisting of hydroxyl group, lower alkoxy group, cycloalkyl group, halogen atom, carboxyl group and lower alkoxycarbonyl group; 
     R 3  : phenyl group which may be substituted with one to four substituent(s) selected from a group consisting of optionally halogen-substituted lower alkyl group, lower alkoxy group, halogen atom, lower alkylthio group, lower alkylsulfinyl group, lower alkanesulfonyl group, carboxyl group, lower alkoxycarbonyl group and carbamoyl group; and 
     R 4  and R 5  : they may be same or different and each is hydrogen atom or lower alkyl.

This application is a 371 of PCT/JP96/03701, filed Dec. 19, 1996.

TECHNICAL FIELD

The present invention relates to pharmaceuticals, more particularly,novel arylethenesulfonamide derivatives having a high affinity toendothelin receptor, pharmaceutically-acceptable salts thereof andpharmaceutical compositions containing the same, particuarly anantagonist to endothelin receptor.

BACKGROUND ART

Endothelin is an endogenous physiologically active peptide consisting of21 amino acids and it has been known that, in endothelin, there arethree isopeptides of ET-1, ET-2 and ET-3 wherein the amino acidsequences are somewhat different.

Endothelin expresses its physiological action by binding to anendothelin receptor on a target cell membrane. For endothelin receptor,it has been clarified until now that there are at least two subtypes andthose subtypes are named ET_(A) and ET_(B), respectively. Thosereceptors differ in their affinity to endothelin. ET_(A) receptor has ahigher affinity to ET-1 and Et-2 than to ET-3 while ET_(B) receptor hasthe affinity of a similar degree to the three types of endothelin.

Endothelin and endothelin receptor are produced and expressed,respectively, in various cells of various organs and varieties ofphysiological actions which are caused by them have been known. Forexample, in blood vessel, ET-1 which is produced and secreted invascular endothelial cells bound ET_(A) receptor on smooth muscle cellsof blood vessel existing near there and contracts the blood vesselstrongly and continuously. On the other hand, vascular endothelial cellsthemselves express ET_(B) receptor and, when ET-1 is bonded thereto,nitrogen monoxide (NO) is produced and released. Nitrogen monoxide hasan action of relaxing the smooth muscle of blood vessel. In fact, whenET-1 is intravenously injected to rat experimentally, long-lastinghypertension is observed after a transient hypotension.

As noted from the physiological action in blood vessel as mentionedabove, ET-1 has an aspect as a physiologically active peptide having avery strong and continuous contraction to blood vessel and, because ofthat, its relation to diseases, particularly to cardiovascular diseases,has been discussed since the time when it was found.

Today, it is pointed out that there is a possibility that an excessivesecretion of endothelin, particularly ET-1 (to be more specific, anincrease in ET-1 concentration either topically or in tissues andcirculating blood), participates not only in cardiovascular diseases butalso in many other diseases. Thus, it was reported to participate, forexample, in essential hypertension, pulmonary hypertension, hypertensioninduced by erythropoietin, hypertension induced by cyclosporin A,bronchial asthma, acute renal failure, chronic renal failure, glomerularnephritis, renal failure induced by cyclosporin, acute myocardialinfarction, unstable angina, congestive heart failure, cerebrovascularspasm mostly after subarachnoid hemorrhage, cerebroischemic disturbance,urinary incontinence, benign prostatic hypertrophy, arteriosclerosis,Raynaud's syndrome, diabetic peripheral circulatory disturbance,diabetic renal diseases, preeclampsia, premature delivery, digestiveulcer, hepatic failure, rheumatism, restenosis after PTCA, chronicrespiratory failure, chronic obstructive pulmonary diseases, corpulmonale, acute respiratory failure, pulmonary edema, ischemic hepaticdisturbance, adult respiratory distress syndrome, interstitialpneumonia, pulmonary fibrosis, glaucoma, osteoarthritis, chronicarticular rheumatism, hepatic cirrhosis, inflammatory bowel diseases(IBD), cancer, etc. (G. M. Rubanyi, M. A. Plokoff, PharmacologicalReviews, vol. 46, no. 3, 325 (1994); Saishin Igaku, vol. 49, no.3, 335(1994); Kidney International, 37, 1487-1491(1990); Lancet, 339,381-385(1992); Cell Mol. Neurobiol., 13, 15-23 (1993); J. Clin.Encocrino. Metab., 76, 378-383 (1993); J. Clin. Pathol., 48(6), 519-524(1995); Chest, 104(2), 476-480(1993); Am. J. Med., 99(3), 155-160(1995); Hepatology, 16, 95-99 (1992); etc.).

Accordingly, pharmaceuticals which inhibit the binding of ET-1 toendothelin receptor by bonding to endothelin receptor, i.e. endothelinreceptor antagonists, can be effective preventive and therapeutic agentsto the diseases as mentioned hereinabove.

With regard to such endothelin receptor antagonists, a series ofbenzenesulfonamide derivatives is disclosed in the Japanese Laid-OpenPatent Publications Hei-05/155,864, Hei-05/222,003, Hei-06/211,810 andHei-07/017,972. In particular, a compound which is represented by thefollowing formula ##STR2## which is disclosed in Example 67 of theJapanese Laid-Open Patent Publication Hei-05/222,003 (generic name:Bosentan) has been reported for its effectiveness and absorption by oraladministration in pathogenic animal models (J. Pharmacol. Exp. Ther.,270(1), 228-2345, 1994; Hypertension, 224, 183-188, 1994; Clin.Pharmacol. Ther., 60, 124-137, 1996).

DISCLOSURE OF THE INVENTION

An object of the present invention is to offer novel compounds havingfar better antagonizing action to endothelin receptor.

The present inventors have proceeded a screening for the compoundshaving a high affinity to endothelin receptor and, as a result, theyhave found that novel arylethenesulfonamide derivatives which aredifferent from conventional compounds in such a respect that arylethenegroup is substituted at sulfonamide of a pyrimidine ring exhibit a highaffinity to endothelin receptor, particularly to ET_(A) receptor, andstrongly antagonize whereupon the present invention has been achieved.

Thus, the present invention relates to a novel arylethenesulfonamidederivative represented by the following formula (I) or apharmaceutically acceptable salt thereof. ##STR3## (In the formula, Ar:optionally substituted aryl group or optionally substituted five- tosix-membered heteroaryl group;

X: oxygen atom, sulfur atom or a group represented by a formula --NH--;

Y: oxygen atom or sulfur atom;

R₁ : hydrogen atom, optionally halogen-substituted lower alkyl group,cycloalkyl group, optionally substituted aryl group or optionallysubstituted five- to six-membered heteroaryl group;

R₂ : lower alkyl group, lower alkenyl group or lower alkynyl group whereeach of which may be substituted with one to three substituent(s)selected from a group consisting of hydroxyl group, lower alkoxy group,cycloalkyl group, halogen atom, carboxyl group and lower alkoxycarbonylgroup;

R₃ : phenyl group which may be substituted with one to foursubstituent(s) selected from a group consisting of optionallyhalogen-substituted lower alkyl group, lower alkoxy group, halogen atom,lower alkylthio group, lower alkylsulfinyl group, lower alkanesulfonylgroup, carboxyl group, lower alkoxycarbonyl group and carbamoyl group;and

R₄ and R₅ : they may be same or different and each is hydrogen atom orlower alkyl group)

Preferred compounds which are preferred in the present invention arearylethenesulfonamide derivatives represented by the above-mentionedformula (I) in which:

Ar is an aryl group which may be substituted with one to fivesubstituent(s) selected from a group consisting of lower alkyl group(said lower alkyl group may be substituted with one to foursubstituent(s) selected from a group consisting of halogen atom, loweralkoxy group, carboxyl group, amino group and mono- or di-loweralkylamino group), lower alkoxy group, lower alkoxycarbonyl group,carboxyl group, halogen atom, nitro group, cyano group, amino group,mono- or di-lower alkylamino group, hydroxyl group and C₁₋₃alkylenedioxy group; or five- to six-membered heteroaryl group which maybe substituted with one to four substituent (s) selected from a groupconsisting of lower alkyl group (said lower alkyl group may besubstituted with one to four substituent(s) selected from a groupconsisting of halogen atom, lower alkoxy group, carboxyl group, aminogroup and mono- or di-lower alkylamino group), lower alkoxy group, loweralkoxycarbonyl group, carboxyl group, halogen atom, nitro group, cyanogroup, amino group, and mono- or di-lower alkylamino group; and

R₁ is hydrogen; lower alkyl group which may be substituted with halogenatom(s); cycloalkyl group; aryl group which may be substituted with oneto five substituent(s) selected from a group consisting of lower alkylgroup (said lower alkyl group may be substituted with one to foursubstituent (s) selected from a group consisting of halogen atom, loweralkoxy group, carboxyl group, amino group and mono- or di-loweralkylamino group), lower alkoxy group, lower alkoxycarbonyl group,carboxyl group, halogen atom, nitro group, cyano group, amino group,mono- or di-lower alkylamino group, hydroxyl group and C₁₋₃alkylenedioxy group; or five- to six-membered heteroaryl group which maybe substituted with one to four substituent(s) selected from a groupconsisting of lower alkyl group (said lower alkyl group may besubstituted with one to four substituent (s) selected from a groupconsisting of halogen atom, lower alkoxy group, carboxyl group, aminogroup and mono- or di-lower alkylamino group), lower alkoxy group, loweralkoxycarbonyl group, carboxyl group, halogen atom, nitro group, cyanogroup, amino group, and mono- or di-lower alkylamino group;

or pharmaceutically aceptable salts thereof.

More preferred compounds are:

(1) arylethenesulfonamide derivatives represented by the above-mentionedformula (I) or salts thereof in which

Ar is aryl group which may be substituted with one to fivesubstituent(s) selected from a group consisting of optionallyhalogen-substituted lower alkyl group, lower alkoxy group, loweralkoxycarbonyl group, carboxyl group, halogen atom, nitro group andcyano group; or five- to six-membered heteroaryl group which may besubstituted with one to four substituent(s) selected from a groupconsisting of lower alkyl group and lower alkoxy group;

X is oxygen atom or a group represented by a formula --NH--;

Y is oxygen atom;

R₁ is optionally halogen-substituted lower alkyl group; cycloalkylgroup; aryl group which may be substituted with one to fivesubstituent(s) selected from a group consisting of optionallyhalogen-substituted lower alkyl group, lower alkoxy group, loweralkoxycarbonyl group, carboxyl group, halogen atom, nitro group, cyanogroup and C₁₋₃ alkylenedioxy group; or five- to six-membered heteroarylgroup which may be substituted with one to four substituent(s) selectedfrom a group consisting of optionally halogen-substituted lower alkylgroup, lower alkoxy group, lower alkoxycarbonyl group, carboxyl group,halogen atom, nitro group and cyano group; and

R₃ is phenyl group which may be substituted with one to foursubstituent(s) selected from a group consisting of optionallyhalogen-substituted lower alkyl group, lower alkoxy group, halogen atom,carboxyl group and lower alkoxycarbonyl group;

(2) arylethenesulfonamide derivatives represented by the formula (I) orpharmaceutically acceptable salts thereof in which

Ar is five- to six-membered heteroaryl group, naphthyl group or phenylgroup which may be substituted with one to five substituent(s) selectedfrom a group consisting of optionally halogen-substituted lower alkylgroup, lower alkoxy group and halogen atom;

R₁ is optionally halogen-substituted lower alkyl group; cycloalkylgroup; phenyl group which may be substituted with one to fivesubstituent(s) selected from a group consisting of optionallyhalogen-substituted lower alkyl group, lower alkoxy group, nitro groupand C₁₋₃ alkylenedioxy group; or five- to six-membered heteroaryl groupwhich may be substituted with one to four substituent(s) selected from agroup consisting of optionally halogen-substituted lower alkyl group andlower alkoxy group;

R₂ is lower alkynyl group or lower alkyl group which may be substitutedwith one to three substituent(s) selected from a group consisting ofhydroxyl group, lower alkoxy group, cycloalkyl group and halogen atom;and

R₃ is phenyl group which may be substituted with one to foursubstituent(s) selected from a group consisting of lower alkyl group,lower alkoxy group and lower alkoxycarbonyl group;

(3) arylethenesulfonamide derivatives represented by the formula (I) orpharmaceutically acceptable salts thereof in which

Ar is optionally lower-alkyl-substituted phenyl group or thienyl group;

X is oxygen atom;

R₁ is phenyl group which may be substituted with lower alkoxy group orfive- to six-membered heteroaryl group which may be substituted withlower alkyl group;

R₂ is lower alkynyl group or lower alkyl group which may be substitutedwith one to three substituent(s) selected from a group consisting ofhydroxyl group and halogen atom; and

R₃ is phenyl group which is substituted with lower alkoxy group(s);

(4) arylethenesulfonamide derivatives represented by the formula (I) orpharmaceutically acceptable salts thereof in which

Ar is phenyl group or thienyl group;

R₁ is pyrimidinyl group;

R₂ is lower alkyl group which may be substituted with halogen atom(s);

R₃ is phenyl group which is substituted with lower alkoxy group(s);

R₄ is hydrogen atom or lower alkyl group; and

R₅ is hydrogen atom; or

(5) arylethenesulfonamide derivatives represented by the formula (I) orpharmaceutically acceptable salts thereof selected from a groupconsisting of the following compounds as well as salts thereof:

N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide,

N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide,

N-[6-(2-fluoroethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide,

N-[6-(2-propynyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide,

N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-1-methyl-2-phenylethenesulfonamide,

N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-1-ethyl-2-phenylethenesulfonamide,and

N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2-thienyl)ethenesulfonamide.

Further, the present invention relates to a pharmaceutical compositionwhich contains the arylethenesulfonamide derivative or pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier and,particularly, it relates to endothelin receptor antagonists. Moreparticularly, it relates to preventive or therapeutic agents fordiseases in which endothelin receptor is participated such as essentialhypertension, pulmonary hypertension, hypertension induced byerythropoietin, hypertension induced by cyclosporin A, bronchial asthma,acute renal failure, chronic renal failure, glomerular nephritis, renalfailure induced by cyclosporin, acute myocardial infarction, unstableangina, congestive heart failure, cerebrovascular spasm mostly aftersubarachnoid hemorrhage, cerebroischemic disturbance, urinaryincontinence, benign prostatic hypertrophy, arteriosclerosis, Raynaud'ssyndrome, diabetic peripheral circulatory disturbance, diabetic renaldiseases, preeclampsia, premature delivery, digestive ulcer, hepaticfailure, rheumatism, restenosis after PTCA, chronic respiratory failure,chronic obstructive pulmonary diseases, cor pulmonale, acute respiratoryfailure, pulmonary edema, ischemic hepatic disturbance, adultrespiratory distress syndrome, interstitial pneumonia, pulmonaryfibrosis, glaucoma, osteoarthritis, chronic articular rheumatism,hepatic cirrhosis, inflammatory bowel diseases (IBD), cancer, etc.

The compound (I) of the present invention will be illustrated in detailas follows.

The term "lower" used in the definitions for the groups in the formula(I) of the present specification means a straight or branched carbonchain having from one to six carbon(s) unless otherwise mentioned.

Accordingly, examples of "lower alkyl group" are methyl group, ethylgroup, propyl group, isopropyl group, butyl group, isobutyl group,sec-butyl group, tert-butyl group, pentyl group, isopentyl group,neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutylgroup, 1,2-dimethylpropyl group, hexyl group, isohexyl group,1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group,1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group,3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group,1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group,1-ethyl-1-methylpropyl group and 1-ethyl-2-methylpropyl group. Amongthem, those having from one to four carbon(s) are preferred and methylgroup, ethyl group, propyl group and isopropyl group are particularlypreferred.

"Lower alkenyl group" is a straight or branched alkenyl group havingfrom two to six carbons and its specific examples are vinyl group, allylgroup, 1-propenyl group, 1-methylvinyl group, 1-butenyl group, 2-butenylgroup, 3-butenyl group, 2-methyl-1-propenyl group, 2-methylallyl group,1-methyl-1-propenyl group, 1-pentenyl group, 2-pentenyl group,3-pentenyl group, 4-pentenyl group, 3-methyl-1-butenyl group,3-methyl-2-butenyl group, 3-methyl-3-butenyl group, 2-methyl-1-butenylgroup, 2-methyl-2-butenyl group, 2-methyl-3-butenyl group,1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 1-methyl-3-butenylgroup, 1,1-dimethylallyl group, 1,2-dimethyl-1-propenyl group,1,2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group,1-ethyl-2-propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenylgroup, 4-hexenyl group, 5-hexenyl group, 1,1-dimethyl-1-butenyl group,1,1-dimethyl-2-butenyl group, 1,1-dimethyl-3-butenyl group,3,3-dimethyl-1-butenyl group, 1-methyl-1-pentenyl group,1-methyl-2-pentenyl group, 1-methyl-3-pentenyl group,1-methyl-4-pentenyl group, 4-methyl-1-pentenyl group,4-methyl-2-pentenyl group and 4-methyl-3-pentenyl group and, among them,alkenyl group having from three to four carbons is preferred.

"Lower alkynyl group" is a straight or branched alkynyl group havingfrom two to six carbons and its examples are ethynyl group, 1-propynylgroup, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynylgroup, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group,3-pentynyl group, 4-pentynyl group, 3-methyl-1-butynyl group,2-methyl-3-butynyl group, 1- methyl-2- butynyl group, 1-methyl-3-butynyl group, 1,1-dimethyl-2-propynyl group, 1-hexynyl group, 2-hexynylgroup, 3-hexynyl group, 4-hexynyl group and 5-hexynyl group. Among them,the alkynyl group having from three to four carbons is preferred.

"Aryl group" in the "optionally substituted aryl group" stands for anaromatic hydrocarbon group. Preferably, it is an aryl group having from6 to 14 carbons and its examples are phenyl group, naphthyl group,indenyl group, anthryl group and phenanthryl group. More preferably, itis phenyl group and naphthyl group.

Those groups may be substituted with one or more substituent(s) or,preferably, with one to five substituent(s). Any substituent may be usedtherefor so far as it is a substituent which is commonly used as asubstituent for aryl group. Preferred examples are lower alkyl group(said lower alkyl may be substituted with from one to foursubstituent(s) selected from a group consisting of halogen atom, loweralkoxy group, carboxyl group, amino group and mono- or di-loweralkylamino group), lower alkoxy group, lower alkoxycarbonyl group,carboxyl group, halogen atom, nitro group, cyano group, amino group,mono- or di-lower alklamino group, hydroxyl group and C₁₋₃ alkylenedioxygroup.

The term "five- to six-membered heteroaryl group" in "optionallysubstituted five- to six-membered heteroaryl group" stands for five- tosix-membered monocyclic heteroaryl group containing from one to fourhetero atom(s) selected from nitrogen atom, sulfur atom and oxygen atomand its specific examples are furyl group, thienyl group, pyrrolylgroup, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolylgroup, oxazolyl group, isoxazolyl group, triazolyl group, oxadiazolylgroup, thiadiazolyl group, tetrazolyl group, pyridyl group, pyrimidinylgroup, pyridazinyl group and pyrazinyl group.

Preferred examples of "optionally substituted five- to six-memberedheteroaryl group" for Ar in the present invention are furyl group,thienyl group, pyrrolyl group, imidazolyl group, thiazolyl group,isothiazolyl group, oxazolyl group and isoxazolyl group and particularlypreferred examples are furyl group and thienyl group. Examples of thepreferred groups for R₁ are furyl group, thienyl group, thiazolyl group,pyridyl group and pyrimidinyl group and, pariticularly preferably,pyrimidinyl group.

Those groups may be substituted with one or more any substituent(s) or,preferably, from one to four substituent(s). Any substituent may be usedso far as it is a substituent which is commonly used as a substituentfor heteroaryl group. Preferred examples are lower alkyl group (saidlower alkyl group may be substituted with from one to four substituent(s) selected from a group consisting of halogen atom, lower alkoxygroup, carboxyl group, amino group and mono- or di-lower alkyl-aminogroup), lower alkoxy group, lower alkoxycarbonyl group, carboxyl group,halogen atom, nitro group, cyano group, amino group or mono- or di-loweralkyl-amino group.

Preferred "cycloalkyl group" is a cycloalkyl group having from three toeight carbons. Its specific examples are cyclopropyl group, cyclobutylgroup, cyclopentyl group, cyclohexyl group, cycloheptyl group andcyclooctyl group and preferred examples are cyclopropyl group,cyclobutyl group, cyclopentyl group and cyclohexyl group.

Examples of "lower alkoxy group" are methoxy group, ethoxy group,propoxy group, isopropoxy group, butoxy group, isobutoxy group,sec-butoxy group, tert-butoxy group, pentyloxy group (amyloxy group),isopentyloxy group, tert-pentyloxy group, neopentyloxy group,2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy groupand hexyloxy group. Among them, those having from one to four carbonsare preferred and methoxy group and ethoxy group are particularlypreferred.

Examples of "halogen atom" are fluorine atom, chlorine atom, bromineatom and iodine atom and preferred examples are fluorine atom andchlorine atom.

Lower alkyl group which is substituted with halogen atom(s) in"optionally halogen-substituted lower alkyl group" is a group in whichone or more hydrogen atom(s) is/are substituted with the above-mentionedhalogen atom(s). Preferably, it is lower alkyl group substituted withone to four halogen atom(s) such as chloromethyl group, fluoromethylgroup, bromomethyl group, iodomethyl group, dichloromethyl group,difluoromethyl group, dibromomethyl group, trichloromethyl group,trifluoromethyl group, 2-chloroethyl group, 2-fluoroethyl group,2-bromoethyl group, 2-iodoethyl group, 2,2-dichloroethyl group,2,2-difluoroethyl group, 2,2-dibromoethyl group, 2,2,2-trichloroethylgroup, 2,2,2-trifluoroethyl group, 1-chloroethyl group, 1-fluoroethylgroup, 1-bromoethyl group, 1-iodoethyl group, 1,2-dichloroethyl group,1,2-difluoroethyl group, 1,1-dibromoethyl group, 1,2,2-trichloroethylgroup, 1,2,2-trifluoroethyl group, 1-bromo-2-chloroethyl group,3-chloropropyl group, 3-fluoropropyl group, 3,3-dichloropropyl group,3,3-difluoropropyl group, 3,3,3-trifluoropropyl group, 4-chlorobutylgroup and 5-fluoropentyl group. Among them, lower alkyl group havingfrom 1 to 3 carbon(s) substituted with from 1 to 3 chlorine or fluorineatom(s) is preferred and particularly preferred one is trifluoroemethylgroup.

"Lower alkoxycarbonyl group" is a group in which an ester is formed fromcarboxyl group and a straight or branched alcohol having from one to sixcarbon(s) and its examples are methoxycarbonyl group, ethoxycarbonylgroup, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonylgroup, isobutoxycarbonyl group, sec-butoxycarbonyl group,tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonylgroup, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group andhexyloxycarbonyl group. Among them, those having from one to fourcarbon(s) are preferred and methoxycarbonyl group and ethoxycarbonylgroup are particularly preferred.

"Lower alkylthio group" is a group in which hydrogen atom of themercapto group is substituted with the above-mentioned "lower alkylgroup" and its specific examples are methylthio group, ethylthio group,propylthio group, isopropylthio group, butylthio group, isobutylthiogroup, pentylthio group, isopentylthio group and hexylthio group. Amongthem, alkylthio group having from one to four carbon(s) are preferredand those having from one to three carbon(s) such as methylthio group,ethylthio group, propylthio group and isopropylthio group areparticularly preferred.

Examples of "lower alkylsulfinyl group" are methylsulfinyl group,ethylsulfinyl group, propylsulfinyl group, isopropylsulfinyl group,butulsulfinyl group, isobutylsulfinyl group, pentylsulfinyl group,isopentylsulfinyl group, hexylsulfinyl group and isohexylsulfinyl group.Among them, alkylsulfinyl group having from one to four carbon(s) arepreferred and those having from one to three carbon(s) such asmethylsulfinyl group, ethylsulfinyl group, propylsulfinyl group andisoproplsulfinyl group are particularly preferred.

Examples of "lower alkanesulfonyl group" are methanesulfonyl group,ethanesulfonyl group, propanesulfonyl group, isopropanesulfonyl group,butanesulfonyl group, isobutanesulfonyl group, pentanesulfonyl group,isopentanesulfonyl group, hexanesulfonyl group and isohexanesulfonylgroup. Among them, alkylsulfonyl groups having from one to fourcarbon(s) are preferred and those having from one to three carbon(s)such as methanesulfonyl group, ethanesulfonyl group, propanesulfonylgroup and isopropanesulfonyl group are particularly preferred.

"Mono- or di-lower alkyl-amino group" is an amino group in which one ortwo hydrogen atom(s) is/are substituted with the above-mentioned alkylgroup(s). In the case of di-lower alkyl-amino group, the two alkylgroups may be either same or different. Examples of the mono-(loweralkyl)-amino group are methylamino group, ethylamino group, propylaminogroup, isopropylamino group, butylamino group, isobutylamino group,sec-butylamino group, tert-butylamino group and pentylamino group whileexamples of di-(lower alkyl)-amino group are dimethylamino group,diethylamino group, dipropylamino group, methylethylamino group,methylpropylamino group, methylisopropylamino group, methylbutylaminogroup, methylisobutylamino group, ethylpropylamino group andethylisopropylamino group.

Specific examples of "C₁₋₃ alkylenedioxy group" are methylenedioxygroup, ethylenedioxy group and propylenedioxy group.

In the compounds of the present invention, there are geometrical isomerssuch as cis- and trans-compounds [or (E) compound and (Z) compound] dueto double bonds and the present invention covers each of the separatedisomer [(E) compound or (Z) compound] and a mixture thereof. In thepresent invention, the compound in which the groups R₄ and R₅ are in atransconfiguration is particularly preferred.

Besides the above, geometrical isomers and tautomers may be presentdepending upon the types of the substituents and the present inventioncovers each of the separated isomers and a mixture thereof.

In addition, compounds of the present invention may have asymmetriccarbon atoms and optical isomers [(R) compound and (S) compound] due tothat may be present. The present invention covers a mixture of thoseoptical isomers and also a compound separated therefrom.

The compound (I) of the present invention may form an acid addition saltor, depending upon the type of the substituent(s), salt with a base maybe formed as well. Such a salt is a pharmaceutically acceptable salt andits specific examples are acid addition salt such as a salt withinorganic acid (for example, hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid) ororganic acid (for example, formic acid, acetic acid, propionic acid,oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid,lactic acid, malic acid, tartaric acid, citric acid, methanesulfonicacid, ethanesulfonic acid, aspartic acid and glutamic acid) and a saltwith base such as inorganic base (for example, sodium, potassium,magnesium, calcium and aluminum) and organic base (for example,methylamine, ethylamine, ethanolamine, lysine and ornithine) as well asammonium salt.

The present invention further covers various kinds of hydrates andsolvates of the compounds (I) of the present invention and salts thereofas well as polymorphic crystals.

(Manufacturing Methods)

Compounds of the present invention and pharmaceutically acceptable saltsthereof may be manufactured by application of various known syntheticmethods utilizing the characteristics based upon the type of theirfundamental skeleton or substituents. At that time, it is sometimeseffective in the manufacturing technique that, depending upon the typeof the functional group, said functional group is substituted with anappropriate protective group, that is a group which can be easilyconverted to said functional group. After that, the protective group isremoved if necessary whereupon a desired compound is afforded. Examplesof such a functional group are hydroxyl group and carboxyl group whileexamples of the protective group therefor are those which are mentioned,for example, in "Protective Groups in Organic Synthesis" (secondedition) by Greene and Wuts and they may be appropriately used dependingupon the reaction conditions.

Representative manufacturing methods of the compounds of the presentinvention will be given as hereunder.

First Manufacturing Method. ##STR4##

(In the formulae, Z is a leaving group such as halogen atom and organicsulfonic acid residue; and M is hydrogen atom or alkali metal atom)

Examples of the sulfonic acid residue are alkanesulfonyloxy group suchas methanesulfonyloxy group and ethanesulfonyloxy group and aromaticsulfonyloxy group such as benzenesulfonyloxy group andtoluenesulfonyloxy group (particularly, p-toluenesulfonyloxy group).

Examples of the alkali metal atom are sodium and potassium.

Compound of the present invention (I) is obtained by the reaction of acompound represented by the formula (II) having an appropriate leavinggroup with alcohol, thiol, amine or alkali metal substituent representedby the formula (III) to conduct etherization or N-alkylation.

It is advantageous to conduct this reaction in such a manner that thecompound (II) is made to react with the compound (III) in an amountcorresponding to the reaction in the presence or absence of an inertsolvent such as benzene, xylene, tetrahydrofuran (THF), ether, dioxane,dimethylformamide (DMF), dimethyl sulfoxide, methylene chloride,dichloromethane, dichloroethane and chloroform in the presence of, ifnecessary, inorganic base such as sodium, sodium hydride, sodiumhydroxide, potassium hydroxide and potassium carbonate or organic basesuch as trimethylamine, triethylamine, pyridine, picoline, lutidine andN,N-dimethylaniline with cooling, at room temperature or with warmingdepending upon the reaction.

Second Manufacturing Method ##STR5##

Compound of the present invention (I) can be manufactured by thereaction of a compound of a formula (IV) having hydroxyl group, mercaptogroup or alkali metal substitute thereof with a compound of a formula(V) having an appropriate leaving group.

The compound can be conducted by the same manner as in the FirstManufacturing Method.

Third Manufacturing Method ##STR6##

Compound of the present invention (I) can be manufactured as follows.Thus, a methanesulfonic acid derivative of a formula (VI) is made toreact with a benzaldehyde derivative of a formula (VII) (the first step)and the resulting alcohol compound of a formula (VIII) is subjected to adehydrating reaction (the second step).

It is advantageous to conduct the first step in such a manner that amethanesulfonic acid derivative (VI) is made to react with abenzaldehyde derivative (VII) in a corresponding amount to the reactionin an inert solvent such as diethyl ether, THF, DMF and benzene in thepresence of a base such as sodium hydride, potassium carbonate, sodiumcarbonate, n-butyl lithium and N,N,N',N'-tetramethylethylenediamine atthe temperature range of from -60° C. to warm temperature.

It is advantageous to conduct the second step in such a manner that thealcohol compound (VIII) is kept at room temperature to with warming inan inert solvent such as benzene and methylene chloride.

If desired, a dehydrating agent such as pyrimidinium p-toulenesulfonate,sulfuric acid and mesyl chloride-triethylamine may be added thereto.

As hereunder, representative methods for the manufacture of startingmaterials will be mentioned in detail.

Manufacturing Method A ##STR7##

The starting compound (II) in the First Manufacturing Method can beprepared by the reaction of pyrimidine dihalide (IX) witharylethenesulfonamide (X) or a salt thereof. The pyrimidine dihalide(IX) can be manufactured by a method mentioned in the Japanese Laid-OpenPatent Publication Hei-05/222,003 or a method similar thereto. Salt (X)of the arylethenesulfonamide can be manufactured by the reaction of afree sulfonamide with an appropriate inorganic base.

Manufacturing Method B ##STR8##

The compound (IV) which is a starting material for the SecondManufacturing Method is prepared by the reaction of a halide of aformula (II) with a sulfurizing agent such as sodium hydrosulfide,hydroxide such as sodium hydroxide or aminating agent such as ammonia.

The compound in which X is a sulfur atom in the above formulae isprepared by a sulfurizing reaction.

It is advantageous to conduct the reaction in such a manner that thehalide (II) is made to react with a sulfurizing agent such as hydrogensulfide and sodium hydrosulfide in an amount corresponding to thereaction in an inert solvent such as toluene, benzene, chloroform, THFand DMF at room temperature to with warming.

Manufacturing Method C ##STR9##

The starting material (VI) in the Third Manufacturing Method is preparedas follows. Thus, the compound (IX) is made to react with amethanesulfonamide derivative (XI) (the first step) and the resultingcompound (XII) is made to react with a compound (III) (the second step).

With regard to the first step, it is advantageous to conduct thereaction under the same conditions as in the Manufacturing Method A.

With regard to the second step, it is advantageous to conduct thereaction under the same conditions as in the First Manufacturing Method.

The reaction product obtained by each of the above-mentionedmanufacturing methods is liberated and purified as a free compound orsalt or solvate thereof such as a hydrate. Salt can be manufactured bymeans of a common salt-forming reaction.

Isolation and purification can be conducted by means of common chemicaloperations such as extraction, concentration, evaporation,crystallization, filtration, recrystallization and variouschromatographic techniques.

Each of the isomers can be separated by common means utilizing thephysico-chemical differences between the isomers. In the case of opticalisomers for example, they can be separated by common racemic resolutionmeans such as fractional crystallization and chromatography. With regardto an optical isomer, it is also possible to synthesize said isomer froman appropriate optically active starting compound.

(Industrial Applicability)

The compounds of the present invention have an affinity to endothelinreceptors and they especially have a high affinity to an ET_(A) receptorwhich is one of subtypes of the endothelin receptors.

Accordingly, the compounds of the present invention exhibit an action ofcompetitively inhibiting the binding of endothelin to receptors and canbe used for the treatment of various diseases in which endothelin isparticipated such as cardiovascular diseases. Examples of such diseasesare essential hypertension, pulmonary hypertension, hypertension inducedby erythropoietin, hypertension induced by cyclosporin A, bronchialasthma, acute renal failure, chronic renal failure, glomerularnephritis, renal insufficiency induced by cyclosporin, acute myocardialinfarction, unstable angina, congestive heart failure, cerebrovascularspasm mostly after subarachnoid hemorrhage, cerebroischemic disturbance,urinary incontinence, benign prostatic hypertrophy, arteriosclerosis,Raynaud's syndrome, diabetic peripheral circulatory disturbance,diabetic renal diseases, preeclampsia, premature delivery, digestiveulcer, hepatic failure, rheumatism, restenosis after PTCA, chronicrespiratory failure, chronic obstructive pulmonary diseases, corpulmonale, acute respiratory failure, pulmonary edema, ischemic hepaticdisturbance, adult respiratory distress syndrome, interstitialpneumonia, pulmonary fibrosis, glaucoma, osteoarthritis, chronicarticular rheumatism, hepatic cirrhosis, inflammatory bowel diseases andcancer.

In addition, the compounds of the present invention show excellentabsorption per os and, further, their sustaining property is good aswell.

Action of the compounds of the present invention was ascertained by thefollowing pharmacological tests.

(1) Test on Inhibition of Binding of Endothelin (ET-1) to Human ET_(A)Receptor

(Operating Method)

cDNA of human ET_(A) receptor was obtained from mRNA of human lung bymeans of an RT-PCR and then transferred into pEF-BOS, a vector forexpression, to prepare plasmid. The prepared plasmid was added to aculture of COS-1 cells (cell strain derived from renal cells of Africangreen monkey) with DEAE-dextran and cDNA of human ET_(A) was transfectedto COS-1 cells. Then it was incubated for three days in a conventionalDMEM (containing 10% of FBS) and the COS-1 cells recovered therefromwere suspended in a hypotonic buffer (10 mM Tris-HCl and 5 mM EDTA; pH7.4) followed by homogenizing the cells using a Polytron. The suspensionin which the cells were homogenized was subjected to anultracentrifugation (100,000G for 30 minutes at 4° C.), the resultingprecipitate (cell membrane fraction) was re-suspended in a Tris buffer(50 mM Tris-HCl and 10 mM MgCl₂ ; pH 7.4) and the suspension waspreserved by freezing at -80° C. (protein amount: about 1 mg/ml).

In conducting the experiment of binding the receptor, the frozen cellmembrane sample was melted and resuspended in an incubation buffer (50mM Tris-HCl, 10 mM MgCl₂ and 0.01% bovine serum albumin; pH 7.4). Themembrane suspension (200 μl) containing 1.25 μg as a membrane protein,25 μl of an incubation buffer containing a test compound in variousconcentrations and 25 μl of [¹²⁵ I] ET-1 (specific activity: 2,200Ci/mM; final concentration: 25 μM) were incubated together at 25° C. forthree hours and then filtered through a glass fiber filter using aBrandel cell harvester. Measurement of radioactivity on the glass fiberfilter was conducted by means of a gamma-counter (counting efficiency:81%). Nonspecific binding was determined by the use of a test buffercontaining 0.1 μM of ET-1. Inhibiting activity of the test compound to[¹²⁵ I] ET-1 was calculated as a concentration (IC₅₀) necessary forinhibiting 50% of the specific binding.

(Results)

The compounds of the present invention strongly suppressed the bindingof ET-1 to human ET_(A) receptor. The result is shown in the followingtable.

                  TABLE 1                                                         ______________________________________                                        Tested Compound IC.sub.50 (nM)                                                ______________________________________                                        Example 1       1.6                                                           Example 2       3.1                                                           Example 6       4.8                                                           Example 8       2.9                                                           Example 13      5.5                                                           Example 22      9.5                                                           Example 27      5.9                                                           Example 32      5.1                                                           Example 33      7.7                                                           Example 34      9.7                                                           Example 37      1.6                                                           Example 38      3.3                                                           Example 39      2.8                                                           Example 42      1.5                                                           Example 45      4.4                                                           Example 47      3.0                                                           ______________________________________                                    

(2) Test on Inhibition of Contraction Induced by ET-1 in RingPreparation Sample of Rat Aorta

(Operating Method)

Ring preparations having a length of 2 mm were prepared from thoracicaorta of male Wistar rats (body weight: 300 to 350 g). Internal cavityof the ring was lightly rubbed by sanitary cotton to remove theendothelium. Each of the ring preparations was mounted with a restingtension of 1 g in an organ bath filled with 10 ml of a Krebs-Henseleitsolution bubbled with 95% of CO₂ and 5% of O₂. The tension generatedfrom the ring preparation was recorded isometrically. After incubatingfor ten minutes together with a test compound, ET-1 was added to theorgan bath in a cumulative manner. The antagonistic activity of the testcompound to ET-1 receptor was calculated as a concentration (pA₂) of thetest compound necessary for transferring the ET-1 concentration-responsecurve two-fold to the right hand direction from the width (dose ratio)of transfer to the right hand direction of the concentration-responsecurve of ET-1 of the test compound of various concentrations.

(Results)

The compounds of the present invention strongly suppressed thecontraction which was induced by ET-1 in artery ring sample of rats.

(3) Test on Inhibition of Big ET-1-induced Pressor Responses in PithedRats

(Operating Method)

Male Wistar rats (body weight: 25-350 g) were anesthetized by sodiumpentobarbital (60 mg/kg, i.p.) and a cannula for artificial ventilationwas inserted into a trachea. Spinal cord was broken by inserting a rodmade of steel thereinto and then the rat was connected to an artificialrespirator. A catheter for measuring the systemic arterial bloodpressure was inserted into a carotid artery while another catheter foradministering big ET-1 was inserted into a femoral vein. After 30minutes from the oral administration of a test compound at doses of 0.1to 10 mg/kg, the rat was pithed and then big ET-1 was intravenouslyadministered at doses of 0.1 to 3.2 nmol/kg in a cumulative manner.Activity of the test compound was evaluated by the dose (DR₂ value)whereby the dose-response curve of pressor responses by big ET-1 to theright hand direction to an extent of two-fold.

(Results)

Oral administration of the compounds of the present invention exhibitedan excellent suppressive action to big ET-1-induced pressor responses inpithed rats. The results are shown in the following Table.

                  TABLE 2                                                         ______________________________________                                        Tested Compound DR.sub.2 (mg/kg)                                              ______________________________________                                        Example 2       0.61                                                          Example 38      0.65                                                          Example 42      1.85                                                          Comparative     32                                                            Compound*                                                                     ______________________________________                                         *Comparative Compound: a compound mentioned in Example 67 of the Japanese     LaidOpen Patent Publication Hei05/222,003 (generic name: Bosentan)            ##STR10##

(4) Test on Inhibition of Big ET-1-induced Pressor Responses inConscious Rats

Male Wistar rats (body weight: 250 to 350 g) were anesthetized by sodiumpentobarbital (60 mg/kg, i.p.). A catheter for measuring the systemicarterial blood pressure was inserted into a carotid artery while anothercatheter for administering big ET-1 was inserted into a jugular vein.Experiment was conducted after two to three days from the operation.Thus, big ET-1 was intravenously administered to conscious rats at adose of 0.5 nmol/kg every one hour. After 30 minutes from the thirdadministration of big ET-1, a test compound was orally administered atdoses of 0.3 to 3 mg/kg. Activity of the test compound was evaluated byan inhibition of big ET-1-induced pressor responses.

(Results)

As a result of the test, the compounds of the present inventionexhibited an excellent suppressive action to big ET-1-induced pressorresponses in conscious rats.

A pharmaceutical composition containing the compound of the presentinvention (I) or salts thereof and a pharmaceutically acceptable carriercan be prepared by a commonly-used method from one or more of thecompound represented by a formula (I) or a salt thereof andpharmaceutical carrier, filler and other additives which are commonlyused for preparing a pharmaceutical preparation. Administration may beeither by oral administration using tablets, pills, capsules, granules,powder and liquid or by parenteral administration using intravenous orintramuscular injections, suppositories and percutaneous agents.

With regard to a solid composition for oral administration according tothe present invention, tablets, powder, granules, etc. are used. In sucha solid composition, one or more active substance(s) is/are mixed withat least one inert diluent such as lactose, mannitol, glucose,hydroxypropylcellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone and magnesium metasilicate aluminate. Thecomposition may also contain additive(s) other than the inert diluentsuch as lubricant (e.g. magnesium stearate, disintegrating agent (e.g.calcium cellulose glycolate), stabilizer (e.g. lactose) and auxiliarysolubilizer (e.g. glutamic acid and aspartic acid). Tablets and pillsmay, if necessary be coated with sugar coat or gastric or enteric filmsuch as sucrose, gelatin, hydroxypropylcellulose andhydroxypropylmethyl-cellulose phthalate.

The liquid composition for oral administration includes pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixiers, etc. andcontains commonly used inert diluents such as pure water and ethanol.Besides the inert diluents, the composition may also contain auxiliaryagents such as moisturizers and suspending agents as well as sweeteners,seasoning agents, aromatic agents and antiseptics.

Injections for parenteral administration include aseptic aqueous ornonaqueous solutions, suspensions and emulsions. Aqueous solutions andsuspensions contain, for example, distilled water for injections and aphysiological saline solution. Nonaqueous solutions and suspensionscontain, for example, propylene glycol, polyethylene glycol, plant oilsuch as olive oil, alcohols such as ethanol, Polysolvate 80 (tradename), etc. Such compositions may further contain auxiliary agents suchas antiseptics, moisturizers, emulsifiers, dispersing agents,stabilizers (e.g. lactose) and auxiliary solubilizers (e.g. glutamicacid and aspartic acid). They can be made aseptic by means of, forexample, filtration passing through a bacterial conserving filter,compounding with aseptic agent, or irradiation. They may also be used bymanufacturing an aseptic solid composition followed by dissolving inaseptic water or aseptic solvent for injection before use.

In the case of oral administration, daily dose is usually from about0.001 to 30 mg/kg body weight or, preferably, 0.1 to 5 mg/kg and this isadministered at a time or by dividing into two to four times a day. Inthe case of an intravenous administration, an appropriate dose per dayis from about 0.001 to 30 mg/kg body weigh and it is administered at atime or by dividing into two or more times a day. The dose may besuitably decided for each case by taking symptom, age, sex, etc. intoconsideration.

BEST MODE FOR CONDUCTING THE INVENTION

The present invention will be illustrated in more detail by means of thefollowing examples. The compounds of the present invention are notlimited to the compounds which are mentioned in the following examplesonly. Incidentally, the methods for the manufacture of the startingcompounds used in the examples will be given as referential examples.

REFERENTIAL EXAMPLE 1

Sodium hydride (60%) (480 mg) was added to a solution of 1.00 g of2-phenylethenesulfonamide in 10 ml of dimethylformamide with ice coolingfollowed by stirring at room temperature for 15 minutes. To thisreaction solution was added 1.91 g of4,6-dichloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine withstirring. The reaction mixture was stirred at room temperature for 2.5hours and poured into a mixture of 1N hydrochloric acid and ice. Theresulting crystals were collected by filtration and pulverized in hotethanol. After allowing to cool, the crystals were collected byfiltration to give 1.91 g ofN-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 2

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(3-methylphenyl)ethenesulfonamidewas prepared by the same manner as in Referential Example 1.

REFERENTIAL EXAMPLE 3

N-[6-Chloro-5-(4-methoxycarbonyl-2-propylphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewas prepared by the same manner as in Referential Example 1.

4,6-Dichloro-5-(4-methoxycarbonyl-2-propylphenoxy)-2-(2-pyrimidinyl)-pyrimidinewhich is a starting material for the above-prepared compound wassynthesized as follows.

To 3.00 g of4,6-dihydroxy-5-(4-methoxycarbonyl-2-propylphenoxy)-2-(2-pyrimidinyl)-pyrimidinewere added 10 ml of phosphorus oxychloride and 1.2 ml of collidine andthe mixture was heated to reflux for four hours with stirring. Thereaction solution was poured into ice water followed by extracting withchloroform. The chloroform layer was washed with a saturated sodiumchloride solution, dried over anhydrous magnesium sulfate and filtered.The filtrate was concentrated in vacuo and the crystals in the residuewere pulverized in ether and collected by filtration to give 1.76 g of4,6-dichloro-5-(4-methoxycarbonyl-2-propylphenoxy)-2-(2-pyrimidinyl)-pyrimidine.

The compounds of the following Referential Examples were synthesized bythe same manner as in Referential Example 1.

REFERENTIAL EXAMPLE 4

N-[6-Chloro-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 5

N-[6-Chloro-2-cyclopropyl-5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 6

N-[6-Chloro-5-(2-methoxyphenoxy)-2-phenyl-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 7

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(4-trifluoromethylphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 8

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-nitrophenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 9

N-[6-Chloro-2-(3,5-dimethoxyphenyl)-5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 10

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-methoxyphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 11

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3,4-methylenedioxyphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 12

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 13

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 14

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 15

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 16

N-[6-Chloro-2-(6-chloro-3-pyridyl)-5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 17

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(6-trifluoromethyl-3-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 18

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-thienyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 19

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-thienyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 20

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-methyl-4-thiazolyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 21

N-[6-Chloro-2-(3-furyl-5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 22

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4pyrimidinyl]-1-methyl-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 23

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-1-ethyl-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 24

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-methylphenyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 25

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-tert-butylphenyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 26

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-chlorophenyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 27

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2-thienyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 28

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-trifluorophenyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 29

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-methoxyphenyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 30

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2-naphthyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 31

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(1-naphthyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 32

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2-chlorophenyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 33

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-methoxycarbonylphenyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 34

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(3-thienyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 35

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(3-chlorophenyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 36

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenyl-1-propylethenesulfonamide.

REFERENTIAL EXAMPLE 37

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-methyl-2-phenylethenesulfonamide.

REFERENTIAL EXAMPLE 38

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2-methylphenyl)ethenesulfonamide.

REFERENTIAL EXAMPLE 39

N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2,4,6-trimethylphenyl)ethenesulfonamide.

EXAMPLE 1

Sodium (230 mg) was dissolved in 5.6 ml of ethylene glycol and 495 mg ofN-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewas added thereto under ice cooling with stirring. The reaction mixturewas stirred at 80° C. for three hours and poured into a mixture of 1Nhydrochloric acid and ice. The crystals separated out therefrom werecollected by filtration and the resulting crystals were purified by asilica gel column chromatography (chloroform-methanol=20:1) to give 500mg ofN-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

To a methanolic solution of 104 mg of the resulting sulfonamidederivative was added 2 ml of 0.1N ethanolic KOH solution followed byconcentrating in vacuo. The resulting solid was pulverized in ether andcollected by filtration to give 84 mg of potassiumN-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidate.

EXAMPLE 2

Sodium (181 mg) was dissolved in 10 ml of methanol and 400 mg ofN-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewas added with stirring at room temperature. The reaction mixture wasstirred at room temperature for three hours and poured into a mixture of1N hydrochloric acid and ice. The crystals separated out therefrom werecollected by filtration and the resulting crystals were purified by asilica gel column chromatography (chloroform-methanol=40:1). Theresulting yellow amorphous substance was crystallized in ether andcollected by filtration to give 273 mg ofN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

Compounds of the following Examples 3 to 6 were prepared by the samemanner as in Example 2.

EXAMPLE 3

N-[6-ethoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 4

N-[5-(2-Methoxyphenoxy)-6-propoxy-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 5

N-[6-Cyclopropylmethoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 6

N-[6-(2-Methoxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 7

Sodium (181 mg) was added to 10 ml of isopropyl alcohol and, after onehour, 100 ml of isopropyl alcohol was added thereto followed by heatingat 60° C. to dissolve. To this reaction solution was added 400 mg ofN-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewith stirring at room temperature. The reaction mixture was stirred atroom temperature for 1.25 hours and then at 60° C. for 45 minutesfollowed by pouring into a mixture of 1N hydrochloric acid and ice. Thesolution was extracted with chloroform and the chloroform layer wasdried over anhydrous magnesium sulfate followed by filtering. Thefiltrate was concentrated in vacuo and the resulting residue waspurified by a silica gel column chromatography (ethyl acetate). Theresulting amorphous substance was crystallized in ether and collected byfiltration to give 57 mg ofN-[6-isopropoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 8

To a solution of 258 mg of fluoroethanol in 20 ml of dimethylformamidewas added 194 mg of sodium hydride (60%) with ice cooling followed bystirring for 30 minutes. To this reaction solution was added 400 mg ofN-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewith stirring under ice cooling followed by stirring for 30 minutes. Thereaction mixture was stirred at room temperature for two hours andpoured into a mixture of 1N hydrochloric acid and ice. This solution wasextracted with chloroform and the chloroform layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was concentratedin vacuo and the resulting residue was purified by a silica gel columnchromatography (chloroform-methanol=40:1). The resulting amorphoussubstance was crystallized in ether and collected by filtration to give240 mg ofN-[6-(2-fluoroethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

Compounds of the following Examples 9 to 10 were prepared by the samemanner as in Example 8.

EXAMPLE 9

N-[6-(2,2-Difluoroethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 10

N-[5-(2-Methoxyphenoxy)-2-(2-pyrimidinyl)-6-(2,2,2-trifluoroethoxy)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 11

Sodium (693 mg) was added to and dissolved in 18.2 ml of aminoethanol.To this reaction solution was added 3.00 g ofN-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewith stirring at room temperature. The reaction mixture was stirred at60° C. for one hour and then at 80° C. for two hours followed by pouringinto a mixture of 1N hydrochloric acid and ice. This solution wasneutralized with a saturated sodium bicarbonate solution and extractedwith ethyl acetate and the ethyl acetate layer was dried over anhydrousmagnesium sulfate and filtered. The filtrate was concentrated in vacuoand the resulting residue was purified by a silica gel columnchromatography (chloroform-methanol=20:1). The resulting amorphoussubstance was pulverized in ether and collected by filtration to give2.40 g ofN-[6-(2-hydroxyethylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 12

Sodium (1.031 g) was dissolved in 20.130 g of 1,3-propanediol and 2.091g ofN-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewas added thereto with stirring at room temperature. The reactionmixture was stirred at room temperature for 50 minutes and then at 60°C. for 50 minutes and poured into a mixture of 1N hydrochloric acid andice. This was extracted with ethyl acetate and the ethyl acetate layerwas dried over anhydrous magnesium sulfate and filtered. The filtratewas concentrated in vacuo and the resulting residue was purified by asilica gel column chromatography (chloroform-methanol=100:1 to 20:1).The resulting syrup was crystallized in ether and collected byfiltration to give 1.817 g ofN-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 13

Sodium (185 mg) was dissolved in 5 ml of 2-propyn-1-ol and 390 mg ofN-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewas added thereto with stirring at room temperature. The reactionmixture was stirred at 60° C. for one hour and poured into a mixture of1N hydrochloric acid and ice. This was extracted with ethyl acetate andthe ethyl acetate layer was dried over anhydrous magnesium sulfate andfiltered. The filtrate was concentrated in vacuo and the resultingresidue was purified by a silica gel column chromatography(chloroform-methanol=100:1 to 30:1). The resulting syrup wascrystallized in ether and collected filtration to give 342 mg ofN-[6-(2-propynyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 14

Sodium (315 mg) was dissolved in 7.7 ml of ethylene glycol and 700 mg ofN-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(3-methylphenyl)ethenesulfonamidewas added thereto with stirring. The reaction mixture was stirred at 90°C. for 30 minutes and poured into a mixture of 1N hydrochloric acid andice. Crystals separated out therefrom were collected by filtration andthe resulting crystals were purified by a silica gel columnchromatography (chloroform-methanol=20:1). The resulting amorphoussubstance was crystallized in ether and collected filtration to give 533mg ofN-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(3-methylphenyl)ethenesulfonamide.

EXAMPLE 15

(a) To 508 mg ofN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewas added 10.3 ml of ethanolic 0.1M potassium hydroxide solutionfollowed by stirring overnight. Crystals separated out therefrom werecollected by filtration and recrystallized from ethanol-water to give330 mg of potassiumN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidate.

(b) To 1.00 g ofN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewere added 10 ml of ethanol-water (4:1) and 110 mg of sodium methoxidefollowed by heating to reflux. To this was added 18 ml of ethanol-water(4:1) so that the crystals were completely dissolved. This was filteredwhen hot, the filtrate was stirred at room temperature and the crystalsseparated out therefrom were collected by filtration. The crystals werewashed with ethanol-water (4:1) to give 80 mg of sodiumN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidatemonohydrate.

EXAMPLE 16

Sodium (356 mg) was dissolved in 20 ml of methanol and 900 mg ofN-[6-chloro-5-(4-methoxycarbonyl-2-propylphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewas added thereto with stirring at room temperature. The reactionmixture was stirred at room temperature for five hours and fortyminutes, at 60° C. for one hour and fifty minutes and at roomtemperature overnight. After that, the mixture was poured into a mixtureof IN hydrochloric acid and ice. Crystals separated out therefrom werecollected by filtration and the resulting crystals were purified by asilica gel column chromatography (chloroform-ethanol=20:1). Theresulting amorphous substance was crystallized in ether and collected byfiltration to give 452 mg ofN-[6-methoxy-5-(4-methoxycarbonyl-2-propylphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 17

Sodium methoxide (336 mg) was added to a solution of 320 mg ofN-[6-chloro-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]-2-phenylethenesulfonamidein 10 ml of N,N-dimethylformamide followed by stirring overnight. Thereaction mixture was poured into a mixture of ice and 1N hydrochloricacid and the solid separated out therefrom was collected by filtration.This solid was purified by a silica gel column chromatography(chloroform) and the resulting oil was crystallized from ether to give210 mg ofN-[6-methoxy-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]-2-phenylethenesulfonamide.

Compounds of the following Examples 18 to 25 were prepared by the samemanner as in Example 17 except that, if necessary, the reaction wasconducted at room temperature or by heating up to the temperature of110° C. Incidentally, the compound forming a salt was synthesized bysubjecting to the same salt-forming reaction as in Example 15.

EXAMPLE 18

PotassiumN-[2-cyclopropyl-6-methoxy-5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-phenylethenesulfonamidate.

EXAMPLE 19

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-phenyl-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 20

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(4-trifluoromethylphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 21

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-nitrophenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 22

N-[2-(3,5-Dimethoxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 23

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-methoxyphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 24

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3,4-methylenedioxyphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 25

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

Compounds of the following Examples 26 to 27 were prepared by the samemanner as in Example 2.

EXAMPLE 26

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 27

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

Compounds of the following Examples 28 to 29 were prepared by the samemanner as in Example 17 except that, if necessary, the reaction wasconducted at room temperature or by heating up to 110° C.

EXAMPLE 28

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 29

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(6-methoxy-3-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 30

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(6-trifluoromethyl-3-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewas prepared by the same manner as in Example 2.

Compounds of the following Examples 31 to 34 were prepared by the samemanner as in Example 17 except that, if necessary, the reaction wasconducted at room temperature or by heating up to 110° C.

EXAMPLE 31

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-thienyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 32

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-thienyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 33

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-methyl-4-thiazolyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 34

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-furyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.

EXAMPLE 35

N-[5-(2-Methoxyphenoxy)-6-(2-propynyloxy)-2-(6-trifluoromethyl-3-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewas prepared by the same manner as in Example 13.

EXAMPLE 36

N-[6-(2-Hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(6-trifluoromethyl-3-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamidewas prepared by the same manner as in Example 1.

Compounds of the following Examples 37 to 42 were prepared by the samemanner as in Example 17 except that, if necessary, the reaction wasconducted at room temperature or by heating up to 110° C. Incidentally,a compound forming a salt was synthesized by subjecting to a furthersalt-forming reaction by the same manner as in Example 15.

EXAMPLE 37

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-1-methyl-2-phenylethenesulfonamide.

EXAMPLE 38

PotassiumN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2pyrimidinyl)-4-pyrimidinyl]-1-ethyl-2-phenylethenesulfonamidate.

EXAMPLE 39

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-methylphenyl)ethenesulfonamide.

EXAMPLE 40

PotassiumN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-tert-butylphenyl)ethenesulfonamidate.

EXAMPLE 41

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-chlorophenyl)ethenesulfonamide.

EXAMPLE 42

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2-thienyl)ethenesulfonamide.

Compounds of the following Examples 43 to 48 were prepared by the samemanner as in Example 2. Incidentally, a compound forming a salt wassynthesized by subjecting to the same salt-forming reaction as inExample 15.

EXAMPLE 43

PotassiumN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-trifluorophenyl)ethenesulfonamidate.

EXAMPLE 44

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-methoxyphenyl)ethenesulfonamide.

EXAMPLE 45

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2-naphthyl)ethenesulfonamide.

EXAMPLE 46

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(1-naphthyl)ethenesulfonamide.

EXAMPLE 47

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2-chlorophenyl)ethenesulfonamide.

EXAMPLE 48

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-carboxyphenyl)ethenesulfonamide.

EXAMPLE 49

Concentrated sulfuric acid (0.1 ml) was added to a solution of 150 mg ofN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-carboxyphenyl)ethenesulfonamidein 10 ml of methanol followed by stirring overnight under a refluxingcondition. The reaction mixture was concentrated in vacuo, 1Nhydrochloric acid was added thereto and the mixture was extracted withethyl acetate. The extract was washed with a saturated saline solution,dried over anhydrous sodium sulfate, filtered and concentrated in vacuoand the resulting solid was recrystallized form ethyl acetate to give102 mg ofN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-methoxycarbonylphenyl)ethenesulfon-amide.

Compounds of the following Examples 50 to 51 were prepared by the samemanner as in Example 2.

EXAMPLE 50

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(3-thienyl)ethenesulfonamide.

EXAMPLE 51

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(3-chlorophenyl)ethenesulfonamide.

EXAMPLE 52

PotassiumN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenyl-1-propylethenesulfonamidatewas prepared by the same manner as in Example 17 and Example 15(a).

Compounds of the following Examples 53 to 55 were prepared by the samemanner as in Example 2.

EXAMPLE 53

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-methyl-2-phenylethenesulfonamide.

EXAMPLE 54

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2-methylphenyl)ethenesulfonamide.

EXAMPLE 55

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2,4,6-trimethylphenyl)ethenesulfonamide.

Structural formulae and physico-chemical properties of the compounds ofthe above Referential Examples are shown in Tables 3 to 4 and structuralformulae and physico-chemical properties of the compounds of Examplesare shown in Tables 5 to 8.

Abbreviations used in the tables have the following meanings.

Ref: Referential Example number

Ex.: Example number

Sa: salt

mp.: melting point

NMR: Nucleomagnetic resonance (DMSO-d₆, TMS internal standard unlessotherwise mentioned) δ:

ana: elementary analysis data

tho: theoretical value

fou: found value

m/z: mass analysis data (m/z)

N.P.: used in the next step without purification

Ph: phenyl group

Pmy: pyrimidinyl group

cPr: cyclopropyl group

nPr: n-propyl group

The: thienyl group

Naph: naphthyl group

tBu: tert-butyl group

Py: pyridyl group

Thi: thiazolyl group

Fur: furyl group

triMeO: trimethoxy group

diMeo: dimethoxy group

triMe: trimethyl group

                                      TABLE 3                                     __________________________________________________________________________     ##STR11##                                                                    Ref                                                                              R.sub.3                                                                             R.sub.1    Ar                                                        __________________________________________________________________________     1 2-MeO--Ph                                                                           2-Pym      Ph   NMR: 3.80(3H, s), 6.83(1H, d), 6.86(1H, t),                                   7.11 (1H, t), 7.13(1H, d), 7.46(3H, m),                                       7.71-7.75(3H, m), 7.87(2H, m), 9.09(2H, d).           2 2-MeO--Ph                                                                           2-Pym      3-Me--Ph                                                                           NMR: 2.32(3H, s), 3.80(3H, s), 6.82(1H, d),                                   6.87(1H, t), 7.09(1H, t), 7.13(1H, d),                                        7.26(1H, d), 7.33(1H, t), 7.52(2H, m),                                        7.73(1H, t) 7.85(2H, m), 9.09(2H, d).                 3 4-MeOOC-                                                                            2-Pym      Ph   NMR: 0.99(3H, t), 1.75(2H, m), 2.84(2H, m),             2-Pr--Ph              3.83(3H, s), 6.76(1H, d), 7.45(3H, m),                                        7.70-7.78(4H, m), 7.80-7.95(3H, m), 9.11(2H,                                  d).                                                   4 2-MeO--Ph                                                                           --CF.sub.3 Ph   NMR: 3.79(3H, s), 6.84-6.90(2H, m), 7.06-                                     7.14(2H, m), 7.41-7.49(4H, m), 7.65-7.74(3H,                                  m).                                                   5 2-MeO--Ph                                                                           cPr        Ph   NMR: 0.92(2H, m), 0.99(2H, m), 2.08(1H, m),                                   3.81(3H, s), 6.62(1H, d), 6.84(1H, t),                                        7.05(1H, t), 7.11(1H, d), 7.44-7.48(4H, m),                                   7.64(1H, d), 7.74-7.76(2H, m), 11.60(1H, brs).        6 2-MeO--Ph                                                                           Ph         Ph   NMR: 3.83(3H, s), 6.77(1H, m), 6.87(1H, m),                                   7.09(1H, m), 7.14(1H, m), 7.42-7.54(6H, m),                                   7.57(1H, d), 7.76-7.78(2H, m), 7.88(1H,                                       d), 8.24-8.26(2H, m) 11.95(1H, brs).                  7 2-MeO--Ph                                                                           4-CF.sub.3 --Ph                                                                          Ph   NMR: 3.82(3H, s), 6.81(1H, m), 6.87(1H, m),                                   7.07(1H, m), 7.14(1H, m), 7.41-7.43(3H, m),                                   7.56(1H, d), 7.78-7.80(2H, m), 7.85-                                          7.91(3H, m), 8.44(2H, d).                             8 2-MeO--Ph                                                                           3-NO.sub.2 --Ph                                                                          Ph   NMR: 3.83(3H, s), 6.82(1H, dd), 6.87(1H, dt),                                 7.09(1H, dt), 7.14(1H, dd), 7.38-7.44(3H,                                     m), 7.57(1H, d), 7.72-7.75(2H, m), 7.82(1H, t),                               7.88(1H, d), 8.39(1H, dd), 8.65                                               (1H, d), 8.99(1H, t).                                 9 2-MeO--Ph                                                                           3,5-diMeO--Ph                                                                            Ph   NMR: 3.80(6H, s), 3.63(3H, s), 6.69(1H, t),                                   6.79(1H, d), 6.87(1H, t), 7.09(1H, t), 7.14(1H,                               d),                                                                           7.40-7.47(5H, m), 7.56(1H, d),                                                7.68-7.72(2H, m), 7.79(1H, d).                       10 2-MeO--Ph                                                                           3-MeO--Ph  Ph   NMR: 3.81(3H, s), 3.83(3H, s), 6.78(1H, dd),                                  6.87(1H, dt), 7.06-7.16(3H, m), 7.37-                                         7.45(4H, m), 7.57(1H, d), 7.72-7.86(5H, m),                                   11.96(1H, brs).                                      11 2-MeO--Ph                                                                            ##STR12## Ph   NMR: 3.82(3H, s), 6.13(2H, 2), 6.75(1H, dd),                                  6.85(1H, dt), 7.01(1H, d), 7.07(1H, dt),                                      7.13(1H, dd), 7.40-7.47(3H, m), 7.55(1H,  d),                                 7.66(1H, d), 7.74-7.77(2H, m), 7.83(1H,  d),                                  7.86(1H, dd), 11.91(1H, brs)                         12 2-MeO--Ph                                                                           3,4,5-tri  Ph   NMR: 3.74(3H, s), 3.80(6H, s), 3.82(3H, s),                   MeO--Ph         6.77(1H, dd), 6.87(1H, dt), 7.08(1H, dt),                                     7.13(1H, dd), 7.39-7.45 (3H, m), 7.57(2H,                                     s), 7.59-7.66(3H, m), 7.74(1H, d).                   13 2-MeO--Ph                                                                           2-Py       Ph   NMR: 3.82(3H, s), 6.83-6.86(2H, m), 7.07(1H,                                  t), 7.13(1H, d), 7.42-7.43(3H, m), 7.63-                                      7.73(5H, m), 8.03(1H, brs), 8.35(1H, d),                                      8.82(1H, d).                                         14 2-MeO--Ph                                                                           4-Py       Ph   NMR: 3.82(3H, s), 6.79(1H, dd), 6.86(1H, dt),                                 7.08(1H, dt), 7.13(1H, dd), 7.42-7.44(3H,                                     m), 7.54(1H, d), 7.76-7.79(2H, m),                                            7.85(1H, d), 8.17(2H, dd), 8.76(2H, dd).             15 2-MeO--Ph                                                                           3-Py       Ph   NMR: 3.83(3H, s), 6.80(1H, d), 6.87(1H, t),                                   7.09(1H, t), 7.14(1H, d), 7.43-7.44(3H, m),                                   7.56-7.59(2H, m), 7.76(2H, m), 7.85(1H,                                       d), 8.58(1H, d), 8.74(1H, m), 9.39(1H, s).           16 2-MeO--Ph                                                                           6-Cl-3-Py  Ph   NMR: 3.82(3H, s), 6.81(1H, dd), 6.86(1H, dt),                                 7.09(1H, dt), 7.14(1H, dd), 7.40-7.47(3H,                                     m), 7.57(1H, d), 7.68(1H, d), 7.75-                                           7.91(2H, m), 7.84(1H, d), 8.57(1H, dd),                                       9.16(1H, d).                                         17 2-MeO--Ph                                                                           6-CF.sub.3 -3-Py                                                                         Ph   NMR: 3.99(3H, s), 6.95(1H, dt), 7.05(1H, dd),                                 7.14(1H, dd), 7.18-7.20(1H, m), 7.24(1H,                                      d), 7.37-7.44(3H, m), 7.47-7.49(2H, m),                                       7.91(1H, d), 8.04(1H, dd), 8.51(1H, d),                                       8.95(1H, brs), 9.06(1H, brs).                        18 2-MeO--Ph                                                                           2-The      Ph   NMR: 3.82(3H, s), 6.77(1H, dd), 6.84(1H, dt),                                 7.07(1H, dt), 7.13(1H, dd), 7.18(1H, t),                                      7.43-7.45(3H, m), 7.55(1H, d), 7.75-                                          7.78(5H, m), 11.94(1H, brs).                         19 2-MeO--Ph                                                                           3-The      Ph   NMR: 3.82(3H, s), 6.75(1H, dd), 6.86(1H, dt),                                 7.07(1H, dt), 7.13(1H, dd), 7.40-7.47(3H,                                     m), 7.55(1H, d), 7.63(1H, dd), 7.67(1H,                                       dd), 7.77-7.80(2H, m), 7.86(1H, d),                                           8.32(1H, dd), 11.86(1H, brs).                        20 2-MeO--Ph                                                                           2-Me-4-Thi Ph   NMR: 2.78(3H, s), 3.81(3H, s), 6.76(1H, dd),                                  6.86(1H, dt), 7.07(1H, dt), 7.13(1H, dd),                                     7.42-7.46(3H, m), 7.74-7.82(3H, m),                                           7.88(1H, d), 8.33(1H, s), 11.97(1H, brs).            21 2-MeO--Ph                                                                           3-Fur      Ph   NMR: 3.82(3H, s), 6.74(1H, dd), 6.86(1H, dt),                                 6.94(1H, d).7.07(1H, dt), 7.13(1H, dd),                                       7.42-7.47(3H, m), 7.55(1H, d), 7.76-                                          7.81(3H, m), 7.84(1H, d), 8.38(1H, s),                                        13.34(1H, brs).                                      __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR13##                                                                    Ref                                                                              R.sub.4                                                                          R.sub.5                                                                          Ar                                                                   __________________________________________________________________________    22 Me H  Ph      NMR: 2.20(3H, s), 3.81(3H, s), 6.82(1H, d), 6.88(1H,                          t), 7.09(1H, t), 7.14(1H, d), 7.34-7.48(6H,                                   m), 7.65(1H, s), 7.94(1H, brs), 8.95(2H, m).                 23 Et H  Ph      NMR: 1.06(3H, m), 2.67(2H, m), 3.81(3H, s), 6.80(1H,                          d), 6.88(1H, t), 7.09(1H, t), 7.14(1H, d),                                    7.36-7.46(5H, m), 7.67(1H, s), 8.01(1H,                                       brs), 8.96(2H, m), 11.99(1H, brs).                           24 H  H  4-Me--Ph                                                                              NMR: 2.33(3H, s), 3.80(3H, s), 6.82(1H, d),                                   6.87(1H, t), 7.08(1H, t), 7.13(1H, t), 7.26(2H,                               d), 7.63(2H, d), 7.72(1H, t), 7.79-7.90(2H,                                   m), 9.19(2H, d).                                             25 H  H  4-tBu--Ph                                                                             NMR: 1.27(9H, t), 3.84(3H, s), 6.82(1H, dd),                                  6.87(1H, dt), 7.09((1H, dt), 7.14(1H, dd),                                    7.45(2H, d), 7.68(2H, d), 7.74(1H, t), 7.80-                                  7.95(2H, m), 9.13(2H, d).                                    26 H  H  4-Cl--Ph                                                                              NMR: 3.80(3H, s), 6.82(1H, dd), 6.87(1H, dt),                                 7.09(1H, dt), 7.13(1H, dd), 7.53(2H, d),                                      7.71(1H, t), 7.79(2H, d), 7.85-7.95(2H, m),                                   9.09(2H, d).                                                 27 H  H  2-The   N.P.                                                         28 H  H  4-CF.sub.3 --Ph                                                                       NMR: 3.81(3H, s), 6.81-6.90(2H, m), 7.06-7.16(2H,                             m), 7.72(1H, dd), 7.84(2H, d), 7.92-8.08(4H,                                  m), 9.11(2H, d).                                             29 H  H  4-MeO--Ph                                                                             NMR: 3.80(6H, s), 6.77-6.90(2H, m), 7.01(2H, d),                              7.06-7.16(2H, m), 7.66-7.90(5H, m), 9.11(2H, d).             30 H  H  2-Naph  NMR: 3.81(3H, s), 6.70-6.90(2H, m), 7.00-7.20(2H,                             m), 7.40-8.25(10H, m), 9.13(2H, d).                          31 H  H  1-Naph  NMR: 3.80(3H, s), 6.85(1H, d), 6.87(1H, dd), 7.09(1H,                         dd), 7.14(1H, d), 7.54-7.66(4H, m),                                           7.91(1H, d), 8.01(2H, d), 8.05(1H, d),                                        8.16(1H, d), 8.60(1H, d), 8.94(2H, d).                       32 H  H  2-Cl--Ph                                                                              N.P.                                                         33 H  H  4-MeOOC--Ph                                                                           NMR: 3.81(3H, s), 3.87(3H, s), 6.82(1H, d), 6.86(1H,                          dd), 7.08(1H, dd), 7.14(1H, d), 7.72(1H,                                      dd), 7.87-8.05(6H, m), 9.10(1H, d).                          34 H  H  3-The   NMR: 3.80(3H, s), 6.82(1H, d), 6.87(1H, dd),                                  7.09(1H, dd), 7.12(1H, d), 7.54(1H, d), 7.62(1H,                              d), 7.64(1H, d), 7.71(1H, dd), 7.97(1H,                                       d), 8.03(1H, s), 9.11(2H, d).                                35 H  H  3-Cl--Ph                                                                              NMR: 3.81(3H, s), 6.82(1H, d), 6.86(1H, dd),                                  7.09(1H, dd), 7.13(1H, d), 7.46-7.53(2H, m),                                  7.71(1H, d), 7.73(1H, dd), 7.85(1H, d),                                       7.87(1H, s), 7.98(1H, d), 9.09(2H, d).                       36 nPr                                                                              H  Ph      NMR: 0.85(3H, t), 1.57(2H, m), 2.60(2H, m), 3.81(3H,                          s), 6.78(1H, d), 6.87(1H, t), 7.09(1H,                                        t), 7.14(1H, d), 7.38-7.45(5H, m), 7.65(1H,                                   brs), 8.02(1H, m), 8.94(2H, m) 12.0(1H, brs).                37 H  Me Ph      N.P.                                                         38 H  H  2-Me--Ph                                                                              NMR: 2.35(3H, s), 3.80(3H, s), 6.68-7.50(7H, m),                              7.60-8.20(4H, m), 9.04(2H, m).                               39 H  H  2,4,6-triMe--Ph                                                                       NMR: 2.23(3H, s), 2.25(6H, s), 3.80(3H, s), 6.82(1H,                          d), 6.88(1H, dd), 6.92(2H, s), 7.10(1H,                                       dd), 7.14(1H, d), 7.54(1H, d), 7.65(1H, dd), 7.84(1H,                         d),                                                                           8.96(2H, d).                                                 __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________     ##STR14##                                                                    Ex.                                                                              --X--R.sub.2                                                                           Ar   Sa                                                           __________________________________________________________________________     1 --OCH.sub.2 CH.sub.2 OH                                                                Ph   K  ana: (C.sub.25 H.sub.22 N.sub.5 O.sub.6 SK.0.8H.sub.2                         O)                                                                              C(%)                                                                             H(%)                                                                             N(%)                                                                             O(%)                                                                             S(%)                                                                             K(%)                                                         tho                                                                             52.31                                                                            4.14                                                                             12.20                                                                            18.95                                                                            5.59                                                                             6.81                                                         fou                                                                             52.50                                                                            4.40                                                                             12.08 5.43                                                            NMR: 3.51(2H, m), 3.84(3H, s), 4.30(2H, m), 4.87(1H,                          m), 6.44(1H, m), 6.74(1H, m), 6.88(1H, m),                                    7.02(1H, d), 7.13(1H, m), 7.33(1H, m),                                        7.40(2H, m), 7.60-7.62(3H, m), 8.20(1H, d),                                   9.02(2H, d)                                                2 --OMe    Ph   -- mp.: 107-109° C.                                                       NMR: 3.82(3H, s), 3.97(3H, s), 6.66(1H, d), 6.82(1H,                          t), 7.02(1H, d), 7.09(1H, d), 7.45(3H, m),                                    7.60-7.80(3H, m), 7.80(1H, d), 7.98(1H, d),                                   9.08(2H, d), 11.46(1H, brs)                                3 --OEt    Ph   -- mp.: 173-174° C.                                                       NMR: 1.07(3H, m), 3.82(3H, s), 4.37(2H, m), 6.74(1H,                          d),                                                                           6.83(1H, t), 7.05-7.10(2H, m), 7.46(3H, m),                                   7.68-7.74(3H, m), 7.82(1H, d), 7.99(1H, d),                                   9.08(2H, d), 11.43(1H, brs)                                4 --O-nPr  Ph   -- mp.: 161-162° C.                                                       NMR: 0.62(3H, t), 1.46(2H, m), 3.81(3H, s), 4.26(2H,                          m),                                                                           6.76(1H, d), 6.83(1H, t), 7.04(1H, t),                                        7.09(1H, d), 7.45(3H, m), 7.67(1H, m),                                        7.73(2H, m), 7.82(1H, d), 7.99(1H, d), 9.07(2H, d),                           11.45(1H, brs)                                             5 --OCH.sub.2 -cPr                                                                       Ph   -- mp.: 134-135° C.                                                       NMR: 0.13(2H, m), 0.35(2H, m), 1.01(1H, m), 3.82(3H,                          s),                                                                           4.19(2H, m), 6.76(1H, d), 6.84(1H, m),                                        7.05(1H, m), 7.10(1H, d), 7.45(3H, m),                                        7.67(1H, m), 7.73(2H, m), 7.81(1H, d), 7.98(1H, d),                           9.06(2H, d), 11.39(1H, brs)                                6 --OCH.sub.2 CH.sub.2 OCH.sub.3                                                         Ph   -- mp.: 129-130° C.                                                       NMR: 3.08(3H, s), 3.40(2H, m), 3.82(3H, s), 4.47(2H,                          m),                                                                           6.77(1H, d), 6.83(1H, m), 7.05(1H, m),                                        7.09(1H, d), 7.45(3H, m), 7.68(1H, m),                                        7.73(2H, m), 7.82(1H, d), 7.99(1H, d), 9.07(2H, m),                           11.41(1H, brs)                                             7 --OCH(CH.sub.3).sub.2                                                                  Ph   -- mp.: 145-147° C.                                                       NMR: 0.95-1.15(6H, m), 3.81(3H, s), 5.32(1H, m),                              6.79(1H, m), 6.84(1H, m), 6.95-7.15(2H, m),                                   7.45(3H, m), 7.45-8.90(4H, m), 7.99(1H, d),                                   9.06(2H, d), 11.34(1H, brs)                                8 --OCH.sub.2 CH.sub.2 F                                                                 Ph   -- mp.: 114-143° C.                                                       NMR: 3.82(3H, s), 4.40-4.70(4H, m), 6.79(1H, d),                              6.83(1H, m), 7.05(1H, m), 7.10(1H, d), 7.45(3H, m),                           7.68(1H, m), 7.74(2H, m), 7.84(1H, d),                                        7.97(1H, d), 9.08(2H, d), 11.47(1H, brs)                   9 --OCH.sub.2 CHF.sub.2                                                                  Ph   -- mp.: 190-191° C.                                                       NMR: 3.81(3H, s), 4.66(2H, t), 6.15(1H, t), 6.79(1H,                          d),                                                                           6.83(1H, m), 7.05(1H, m), 6.84(1H, d),                                        7.45(3H, m), 7.70(1H, m), 7.74(2H, m),                                        7.86(1H, d), 7.97(1H, D), 9.09(2H, d), 11.57(1H,                              brs)                                                      10 --OCH.sub.2 CF.sub.3                                                                   Ph   -- mp.: 204-205° C.                                                       NMR: 3.81(3H, s), 5.03(2H, q), 6.80-6.86(2H, m),                              7.04-7.10(2H, m), 7.45(3H, m), 7.69(1H, m),                                   7.74(2H, m), 7.87(1H, d), 7.95(1H, d), 9.09(2H, d),                           11.67(1H, brs)                                            11 --NHCH.sub.2 CH.sub.2 OH                                                               Ph   -- ana: (C.sub.25 H.sub.24 N.sub.6 O.sub.5 S.0.3H.sub.2                          O)                                                                              C(%)                                                                             H(%)                                                                             N(%)                                                                             O(%)                                                                             S(%)                                                            tho                                                                             57.09                                                                            4.71                                                                             15.98                                                                            16.12                                                                            6.10                                                            fou                                                                             56.96                                                                            4.44                                                                             15.76 6.10                                                            NMR(DMSO-d.sub.6, 100° C.): 3.57(4H, m),                               3.88(3H, s),                                                                  4.47(1H, m), 6.30-6.70(6H, m), 6.70-6.95(7H, m),                              9.06(2H, m), 13.26(1H, brs)                               12 --O(CH.sub.2).sub.3 OH                                                                 Ph   -- mp.: 190-191° C.                                                       NMR(CDCl.sub.3): 1.86-1.92(2H, m), 3.56(2H, d,                                J=4.9Hz),                                                                     3.98(3H, s), 4.80(2H, t, J=5.5Hz), 5.20(1H,                                   brs), 6.89(1H, t), 7.00(1H, d, J=7.3Hz),                                      7.10-7.14(2H, m), 7.36-7.40(4H, m), 7.57-7.58(2H,                             m),                                                                           7.62(1H, d), 8.04(1H, d), 8.81(1H, brs),                                      8.95(2H, d, J=4.3Hz)                                      13 --OCH.sub.2 C.tbd.CH                                                                   Ph   -- mp: 183-185° C.                                                        NMR(CDCl.sub.3): 2.45(1H, t, J=2.4Hz), 4.00(3H, s),                           5.22(2H, d, J=2.4Hz), 6.91(1H, t), 7.00(1H, d,                                J=7.3Hz), 7.14(1H, t), 7.25-7.26(1H, m),                                      7.38-7.41(4H, m), 7.56-7.57(2H, m), 7.63(1H, m),                              7.98(1H, d), 8.93(1H, s), 8.95(2H, d, J=4.9Hz)            14 --OCH.sub.2 CH.sub.2 OH                                                                3-Me--Ph                                                                           -- mp.: 167-169° C.                                                       NMR: 2.34(3H, s), 3.50(2H, m), 3.83(3H, s), 4.37(2H,                          m),                                                                           4.69(1H, m), 6.79-6.83(2H, m), 7.09-7.10(2H, m),                              7.26(1H, d), 7.33(1H, t), 7.53(2H, m),                                        7.69(1H, m) 7.77(1H, d), 7.95(1H, d), 9.08(2H, d),                            11.43(1H, brs)                                            15 --OMe    Ph   K  mp.: 201-203° C.                                   (a)                 NMR: 3.80(3H, s), 3.85(3H, s), 6.40(1H, dd, J=1.6,                            8.0Hz),                                                                       6.73(1H, dt, J=1.6, 8.0Hz), 6.87(1H, dt, J=1.6,                               8.0Hz),                                                                       7.01(1H, dd, J=1.6, 8.0Hz), 7.12(1H, d, J=16Hz),                              7.31(1H, m), 7.38-7.42(2H, m), 7.57-7.63(3H, m),                              8.21(1H, d, J=16Hz), 9.03(2H, d, J=4.8Hz).                15 --OMe    Ph   Na mp: 192-195° C.                                    (b)                 NMR: 3.82(3H, s), 3.85(3H, s), 6.41(1H, dd, J=1.6,                            7.6Hz),                                                                       6.74(1H, t, J=7.6Hz), 6.88(1H, dt, J=1.6, 7.6Hz),                             7.02(1H, d, J=7.6Hz), 7.13(1H, d, J=16Hz),                                    7.31(1H, m), 7.35-7.41(2H, m), 7.51-7.56(2H, m),                              7.63(1H, t, J=4.8Hz), 7.87(1H, d, J=16Hz),                                    9.01(2H, d, J=4.8Hz)                                      __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________     ##STR15##                                                                    Ex.                                                                           X-R.sub.2                                                                             Ar  Sa                                                                __________________________________________________________________________    16  --OMe                                                                             Ph  --  mp.:                                                                              227-230° C.                                                        NMR:                                                                              0.97(3H, t), 1.71(2H, m), 2.80(2H, m), 3.82                                   (3H, s), 3.88(3H, s), 6.64(1H, m), 7.45(3H,                                   m), 7.60-7.80(5H, m), 7.84(1H, s), 7.95(1H,                                   m), 9.07(2H, d), 11.70(1H, brs)                           __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________     ##STR16##                                                                    Ex.                                                                           X-R.sub.2                                                                              R.sub.1   Sa                                                         __________________________________________________________________________    17 --OMe CF.sub.3  -- NMR:                                                                              3.80(3H, s), 3.83(3H, s), 6.73(1H, m), 6.81                                   (1H, m), 7.03(1H, m), 7.08(1H, m), 7.46-                                      7.47(3H, m), 7.66-7.70(3H, m), 11.79(1H, m).                              m/z:                                                                              482(FAB, M.sup.+  + 1)                              18 --OMe cPr       K  NMR:                                                                              0.84(2H, m), 0.92(2H, m), 1.88(1H,m), 3.70                                    (3H, s), 3.82(3H, s), 6.34(1H m), 6.73(1H,                                    m), 6.85(1H, m), 6.98(1H, m), 7.38-7.41                                       (4H, m), 7.52(2H, m).                                                     m/z:                                                                              530(FAB, M.sup.+  + K)                              19 --OMe Ph        -- mp.:                                                                              147-148° C.                                                        NMR:                                                                              3.85(3H, s), 3.92(3H, s), 6.66(1H, d), 6.82                                   (1H, t), 7.04(1H, t), 7.10(1H, d), 7.43-                                      7.51(6H, m), 7.56(1H, d), 7.74-7.76(2H, d)                                    7.81(1H, d), 8.29(2H, d), 11.23(1H, brs)            20 --OMe 4-CF.sub.3 -Ph                                                                          -- mp.:                                                                              143-144° C.                                                        NMR:                                                                              3.85(3H, s), 3.94(3H, s), 6.69(1H, d), 6.83                                   (1H, t), 7.03(1H, t), 7.10(1H, d), 7.42-                                      7.43(3H, m), 7.56(1H, d), 7.69-7.84(3H, m),                                   8.48(2H, d), 11.36(1H, s).                          21 --OMe 3-NO.sub.2 -Ph                                                                          -- mp.:                                                                              235-236° C.                                                        NMR:                                                                              3.84(3H, s), 3.96(3H, s), 6.71(1H, d), 6.83                                   (1H, m), 7.03(1H, m), 7.10(1H, m), 7.38-                                      7.44(3H, m), 7.56(1H, d), 7.68-7.74(2H, m),                                   7.77-7.83(2H, m), 8.36(1H, m), 8.70(1H,                                       m), 9.05(1H, t), 11.38(1H, brs).                    22 --OMe 3,5-diMeO-                                                                              -- mp.:                                                                              164-165° C.                                           Ph           NMR:                                                                              3.79(6H, s), 3.84(3H, s), 3.92(3H, s), 6.64-                                  6.70(2H, m), 6.82(1H, t), 7.73((1H, t),                                       7.09(1H, d), 7.40-7.48(5H, m), 7.56(1H, d),                                   7.64-7.70(2H, m), 7.72(1H, d), 11.23(1H, brs).      23 --OMe 3-MeO-Ph  -- mp.:                                                                              161-162° C.                                                        NMR:                                                                              3.80(3H, s), 3.85(3H, s), 3.92(3H, s), 6.66                                   (1H, d), 6.82(1H, t), 7.03(1H, t), 7.05-                                      7.13(2H, m), 7.38(1H, t), 7.35-7.45(2H, m),                                   7.56(1H, d), 7.70-7.74(2H, m), 7.77(1H,                                       d), 7.84(1H, m), 7.88(1H, d), 11.26(1H, s).         24 --OMe                                                                                ##STR17##                                                                              -- mp.:  NMR:                                                                        158-159° C.  3.85(3H, s), 3.90(3H, s),                                 6.11(2H, s),  6.64(1H, d), 6.83(1H, t),                                       6.97-7.04(2H, m),  7.09(1H, d), 7.42-7.47(3H,                                 m), 7.54(1H, d),  7.71-7.79(4H, m), 7.90(1H,                                  d),  11.20(1H, s).                                  25 --OMe 3,4,5-tri -- mp.:                                                                              153-154° C.                                           MeO-Ph       NMR:                                                                              3.73(3H, s), 3.78(6H, s), 3.84(3H, s), 3.94                                   (3H, s), 6.64(1H, dd), 6.82(1H, dt), 7.03                                     (1H, dt), 7.09(1H, dd), 7.38-7.46(3H, m),                                     7.56-7.72(6H, m), 11.26(1H, s).                     26 --OMe 2-Py      -- mp.:                                                                              88-90° C.                                                          m/z:                                                                              530(FAB, M.sup.+  + 1)                              27 --OMe 4-Py      -- mp.:                                                                              212-214° C.                                                        NMR:                                                                              3.84(3H, s), 3.93(3H, s), 6.69(1H, dd), 6.82                                  (1H, dt), 7.03(1H, dt), 7.10(1H, dd), 7.43-                                   7.45(3H, m), 7.56(1H, d), 7.77-7.79(2H,                                       m), 7.84(1H, d), 8.16(2H, dd), 8.71(2H,                                       dd), 11.43(1H, brs).                                28 --OMe 3-Py      -- mp.:                                                                              168-169° C.                                                        NMR:                                                                              3.84(3H, s), 3.94(3H, s), 6.68(1H, d), 6.82                                   (1H, t), 7.03(1H, t), 7.10(1H, d), 7.43-                                      7.44(3H, m), 7.52(1H, m), 7.57(1H, d), 7.74-                                  7.75(2H, m), 7.80(1H, d), 8.56(1H, d), 8.70                                   (1H, d), 9.44(1H, s), 11.38(1H, s).                 29 --OMe 6-MeO-3-Py                                                                              -- mp.:                                                                              156-157° C.                                                        NMR:                                                                              3.85(3H, s), 3.91(3H, s), 6.65(1H, dd), 6.82                                  (1H, dt), 6.89(1H, d), 7.02(1H, dt), 7.09                                     (1H, dd), 7.41-7.47(3H, m), 7.55(1H, d),                                      7.72-7.79(3H, m), 8.47(1H, dd), 9.07(2H,                                      d), 11.27(1H, s).                                   30 --OMe 6-CF.sub.3 -3-Py                                                                        -- mp.:                                                                              169-170.5° C.                                                      NMR:                                                                              3.84(3H, s), 3.93(3H, s), 6.70(1H, d), 6.82                                   (1H, t), 7.03(1H, t), 7.10(1H, dd), 7.42-                                     7.44(3H, m), 7.72-7.76(3H, m), 7.85(1H, d),                                   8.38(1H, d), 8.55(1H, d), 9.18(1H, s),                                        11.49(1H, brs).                                     31 --OMe 2-The     -- mp.:                                                                              180-181° C.                                                        NMR:                                                                              3.84(3H, s), 3.87(3H, s), 6.65(1H, dd), 6.81                                  (1H, dt), 7.02(1H, t), 7.09(1H, dd), 7.17                                     (1H, dd), 7.42-7.46(3H, m), 7.56(1H, d),                                      7.72-7.80(3H, m), 7.86(1H, dd), 11.27(1H, s).       32 --OMe 3-The     -- mp.:                                                                              162-163° C.                                                        NMR:                                                                              3.84(3H, s), 3.89(3H, s), 6.63(1H, dd), 6.81                                  (1H, dt), 7.02(1H, dt), 7.09(1H, dd), 7.40-                                   7.46(3H, m), 7.54(1H, d), 7.62(1H, dd),                                       7.70-7.80(4H, m), 8.27(1H, dd), 11.17(1H, s).       33 --OMe 2-Me-4-Thi                                                                              -- mp.:                                                                              90-92° C.                                                          NMR:                                                                              2.80(3H, s), 3.83(3H, s), 3.89(3H, s), 6.62                                   (1H, d), 6.81(1H, t), 7.01(1H, t), 7.09                                       (1H, d), 7.42-7.48(3H, m), 7.74-7.84(3H, m),                                  7.91(1H, d), 8.30(1H, s), 11.31(1H, s).             34 --OMe 3-Fur     -- mp.:                                                                              170-171° C.                                                        NMR:                                                                              3.84(3H, s), 3.86(3H, s), 6.63(1H, dd), 6.81                                  (1H, dt), 6.95(1H, d), 7.01(1H, dt), 7.08                                     (1H, dd), 7.42-7.46(3H, m), 7.54(1H, d),                                      7.72-7.78(4H, m), 8.33(1H, d), 11.14(1H, s).        35 --OCH.sub.2 C.tbd.                                                                  6-CF.sub.3 -3-Py                                                                           mp.:                                                                              172-174° C.                                     CH                 NMR:                                                                              3.49(1H, s), 3.84(3H, s), 5.10(2H, s), 6.72                                   (1H, d), 6.83(1H, t), 7.05(1H, t), 7.11                                       (1H, dd), 7.42-7.44(3H, m), 7.75(3H, m), 7.87                                 (1H, d), 8.40(1H, d), 8.57(1H, d), 9.20                                       (1H, s), 11.57(1H, brs).                            36 --OCH.sub.2 CH.sub.2                                                                6-CF.sub.3 -3-Py                                                                           mp.:                                                                              175-176.5° C.                                   OH                 NMR:                                                                              3.52(2H, t), 3.83(3H, s), 4.41(2H, t), 6.80-                                  6.86(2H, m), 7.05(1H, dt), 7.10(1H, d),                                       7.42-7.43(3H, m), 7.72-7.76(3H, m), 7.86                                      (1H, d), 8.37(1H, d), 8.53(1H, d), 8.17(1H,                                   s),                                                                           11.36(1H, s).                                       __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________     ##STR18##                                                                    Ex.                                                                              R.sub.4                                                                          R.sub.5                                                                          Ar     Sa                                                            __________________________________________________________________________    37 Me H  Ph     -- mp.:                                                                              148-149° C.                                                        NMR:                                                                              2.21(3H, s), 3.83(3H, s), 4.01(3H, s), 6.65                                   (1H, d), 6.83(1H, t), 7.03(1H, t), 7.09(1H d),                                7.22-                                                                         7.41(5H, m), 7.61(1H, m), 7.87(1H, s), 9.18                                   (2H, d), 11.29(1H, brs).                               38 Et H  Ph     K  NMR:                                                                              1.00(3H, t), 2.39(2H, q), 3.78(3H, s), 3.83                                   (3H, s), 6.41(1H, d), 6.73(1H, t), 6.87(1H, t),                               7.00(1H, d), 7.17(2H, d), 7.24(1H, m), 7.30-                                  7.35(3H, m), 7.54(1H, t), 8.89(2H, d).                                    m/z:                                                                              596(FAB, M.sup.+  + K)                                 39 H  H  4-Me-Ph                                                                              -- mp.:                                                                              165-166° C.                                                        NMR:                                                                              2.33(3H, s), 3.83(3H, s), 4.01(3H, s), 6.66(1H,                               d), 6.82(1H, t), 7.03(1H, t), 7.09(1H, t), 7.27                               (2H, d), 7.62(2H, d), 7.69(1H, m), 7.72(1H, d),                               7.92(1H, d), 9.09(2H, d), 11.42(1H, brs).              40 H  H  4-tBu-Ph                                                                             K  NMR:                                                                              1.28(9H, s), 3.80(3H, s), 3.98(3H, s), 6.39                                   (1H, d), 6.73(1H, t), 6.87(1H, t), 7.01(1H, d),                               7.12(1H, d), 7.41(2H, d), 7.50(2H, d), 7.62(1H,                               t), 8.13(1H, d), 9.05(2H, d).                                             m/z:                                                                              624(FAB, M.sup.+  + K)                                 41 H  H  4-Cl-Ph                                                                              -- NMR:                                                                              3.80(3H, s), 4.01(3H, s), 6.67(1H, d), 6.82                                   (1H, t), 7.03(1H, t), 7.09(1H, d), 7.38(2H, d),                               7.67(1H, m), 7.79-7.95(3H, m), 8.02(1H, d),                                   9.09(2H, d), 11.52(1H, brs).                                              m/z:                                                                              526(FAB, M.sup.+  + 1)                                 42 H  H  2-The  -- NMR:                                                                              3.83(3H, s), 3.90(3H, s), 6.66(1H, d), 6.82                                   (1H, t), 7.03(1H, t), 7.09(1H, d), 7.16(1H, t),                               7.58(1H, m), 7.67-7.71(2H, m), 7.76(1H, d),                                   8.03(1H, d), 9.10(2H, d), 11.48(1H, brs).                                 m/z:                                                                              498(FAB, M.sup.+  + 1)                                 43 H  H  4-CF.sub.3 -Ph                                                                       K  NMR:                                                                              3.80(3H, s), 3.85(3H, s), 6.40(1H, d), 6.74                                   (1H, dd), 6.88(1H, dd), 7.02(1H, d), 7.20(1H, d),                             7.62(1H, dd), 7.79(2H, d), 7.85(2H, d), 8.43                                  (1H, d), 9.06(2H, d).                                                     m/z:                                                                              635(FAB, M.sup.+  + K - 1)                             44 H  H  4-MeO-Ph                                                                             -- NMR:                                                                              3.80(3H, s), 3.83(3H, s), 3.89(3H, s), 6.60-                                  8.00(11H, m), 9.10(2H, d).                                                m/z:                                                                              520(FAB, M.sup.+  + 1)                                 45 H  H  2-Naph -- NMR:                                                                              3.83(3H, s), 3.90(3H, s), 6.60-7.20(4H, m),                                   7.40-8.30(10H, m), 9.13(2H, d).                                           m/z:                                                                              540(FAB, M.sup.+  + 1)                                 46 H  H  1-Naph -- NMR:                                                                              3.83(3H, s), 3.89(3H, s), 6.69(1H, d), 6.82                                   (1H, dd), 7.03(1H, dd), 7.10(1H, d), 7.53-7.64                                (4H, m), 7.97-8.08(4H, m), 8.14(1H, d), 8.53                                  (1H, d), 8.93(2H, d), 11.51(1H, s).                                       m/z:                                                                              540(FAB, M.sup.+  - 1)                                 47 H  H  2-Cl-Ph                                                                              -- mp.:                                                                              97-98° C.                                                          NMR:                                                                              3.83(3H, s), 3.91(3H, s), 6.68(1H, d), 6.82                                   (1H, t), 7.03(1H, t), 7.09(1H, d), 7.46-7.50                                  (2H, m), 7.57(1H, brd), 7.66(1H, brs), 7.95(2H,                               brs), 8.14(1H, brd), 9.02(2H, brs).                    48 H  H  4-HOOC-Ph                                                                            -- mp.:                                                                              >250° C.                                                           NMR:                                                                              3.83(3H, s), 3.90(3H, s), 6.68(1H, d), 6.82                                   (1H, dd), 7.03(1H, dd), 7.10(1H, d), 7.69(1H, d),                             7.79-7.93(3H, m), 8.05(2H, d), 8.12(1H, d),                                   9.10(2H, d), 11.59(1H, s), 13.15(1H, s).               49 H  H  4-MeOOC-                                                                             -- mp.:                                                                              178-179° C.                                              Ph        NMR:                                                                              3.83(3H, s), 3.87(3H, s), 3.89(3H, s), 6.67                                   (1H, d), 6.81(1H, dd), 7.02(1H, dd), 7.09(1H, d),                             7.69(1H, dd), 7.80-7.96(3H, m), 8.03(2H, d),                                  8.13(1H, d), 9.09(2H, d), 11.60(1H, s).                50 H  H  3-The  -- NMR:                                                                              3.83(3H, s), 3.89(3H, s), 6.66(1H, d), 6.82                                   (1H, dd), 7.03(1H, dd), 7.10(1H, d), 7.53(1H, d),                             7.62-7.76(3H, m), 7.88(1H, d), 8.01(1H, s),                                   9.09(2H, d), 11.42(1H, s).                                                m/z:                                                                              498(FAB, M.sup.+  + 1), 520(FAB, M.sup.+  + Na)        51 H  H  3-Cl-Ph                                                                              -- NMR:                                                                              3.83(3H, s), 3.90(3H, s), 6.68(1H, d), 6.82                                   (1H, dd), 7.03(1H, dd), 7.09(1H, d), 7.46-7.52                                (2H, m), 7.66-7.75(2H, m), 7.80(1H, d), 7.87                                  (1H, s), 8.11(1H, d), 9.08(2H, d), 11.59(1H, s).                          m/z:                                                                              526(FAB, M.sup.+  + 1), 548(FAB, M.sup.+  + Na)        52 nPr                                                                              H  Ph     K  NMR:                                                                              0.70(3H, t), 1.46(2H, m), 2.34(2H, m), 3.77                                   (3H, s), 3.84(3H, s), 6.39(1H, dd), 6.72(1H, dt),                             6.87(1H, dt), 7.01(1H, dd), 7.14-7.17(2H,                                     m), 7.23(1H, m), 7.30-7.34(2H, m), 7.37(1H, s),                               7.53(1H, t), 8.85(2H, d).                                                 mn/z:                                                                             610(FAB, M.sup.+  + K)                                 53 H  Me Ph     -- NMR:                                                                              2.23(3H, d), 3.79(3H, s), 3.85(3H, s), 6.40                                   (1H, dd), 6.73(1H, dt), 6.87(1H, dt), 7.01(1H,                                dd), 7.18(1H, d), 7.26-7.34(3H, m), 7.52-7.55                                 (2H, m), 7.61(1H, t), 8.98(2H, d).                                        m/z:                                                                              528(FAB, M.sup.+  + Na)                                54 H  H  2-Me-Ph                                                                              -- NMR:                                                                              2.27(3H, s), 3.82(3H, s), 3.84(3H, s), 6.40                                   (1H, dd), 6.62-7.08(3H, m), 7.20-7.39(4H, m),                                 7.56-7.67(2H, m), 8.02(1H, brd)                                           m/z:                                                                              506(FAB, M.sup.+  + 1).                                55 H  H  2,4,6-tri                                                                            -- NMR:                                                                              2.24(9H, s), 3.82(3H, s), 3.91(3H, s), 6.55-                    Me-Ph         7.20(7H, m), 7.50-7.90(2H, m), 8.96(2H, d).                               m/z:                                                                              534(FAB, M.sup.+  + 1), 556(FAB, M.sup.+  +            __________________________________________________________________________                           Na)                                                

The compounds whose chemical structural formulae are given in thefollowing Table 9 can be easily manufactured by almost the same methodmentioned in the above Examples or Manufacturing Methods or by applyingsome modifications thereto which are obvious to the persons skilled inthe art.

Abbreviations in the table have the same meanings which were definedalready. Incidentally, "Co." in the table means a compound number.

                                      TABLE 9                                     __________________________________________________________________________     ##STR19##                                                                    Co. R.sub.2 -X-                                                                       R.sub.4                                                                          R.sub.5                                                                          Ar      Co. R.sub.2 -X-                                                                       R.sub.4                                                                          R.sub.5                                                                          Ar                                        __________________________________________________________________________    1   MeO H  H  2-Fur   16  MeO Me H  2-The                                     2   MeO H  H  3-Fur   17  MeO Me H  3-The                                     3   MeO H  H  2-Thi   18  MeO Et H  2-The                                     4   MeO H  H  4-Thi   19  MeO Et H  3-The                                     5   MeO H  H  5-Thi   20  MeS H  H  Ph                                        6   MeO H  H  2-Py    21  MeS Me H  Ph                                        7   MeO H  H  3-Py    22  MeS Et H  Ph                                        8   MeO H  H  4-Py    23  MeS H  H  2-The                                     9   MeO H  H  5-Pym   24  MeS H  H  3-The                                     10  MeO H  H  2-MeO-Ph                                                                              25  MeNH                                                                              H  H  Ph                                        11  MeO H  H  3-MeO-Ph                                                                              26  MeNH                                                                              Me H  Ph                                        12  MeO H  H  2-CN-Ph 27  MeNH                                                                              Et H  Ph                                        13  MeO H  H  3-CN-Ph 28  MeNH                                                                              H  H  2-The                                     14  MeO H  H  3-Me-Ph 29  MeNH                                                                              H  H  3-The                                     15  MeO H  H  3,4-diMeO-Ph                                                    __________________________________________________________________________

What is claimed is:
 1. An arylethenesulfonamide compound represented bythe following formula (I) or a pharmaceutically acceptable salt thereof:##STR20## in which Ar is a thienyl group or an aryl group which isunsubstituted or substituted with one to five identical or differentsubstituents selected from the group consisting of lower alkyl group,lower alkoxy group, lower alkoxycarbonyl group, carboxyl group, halogenatom, nitro group, cyano group, amino group, mono-lower alkylaminogroup, di-lower alkylamino group, hydroxyl group and C₁₋₃ alkylenedioxygroup, wherein said lower alkyl group is unsubstituted or substitutedwith one to four identical or different substituents selected from thegroup consisting of halogen atom, lower alkoxy group, carboxyl group,amino group, mono-lower alkylamino group, and di-lower alkylaminogroup;X is oxygen atom, sulfur atom or a group represented by --NH--; Yis oxygen atom or sulfur atom; R₁ is hydrogen atom, lower alkyl groupwhich is unsubstituted or substituted with one or more identical ordifferent halogen atoms, cycloalkyl group, aryl group which isunsubstituted or substituted with one to five identical or differentsubstituents selected from the group consisting of lower alkyl group,lower alkoxy group, lower alkoxycarbonyl group, carboxyl group, halogenatom, nitro group, cyano group, amino group, mono-lower alkylaminogroup, di-lower alkylamino group, hydroxyl group and C₁₋₃ alkylenedioxygroup, wherein said lower alkyl group is unsubstituted or substitutedwith one to four identical or different substituents selected from thegroup consisting of halogen atom, lower alkoxy group, carboxyl group,amino group, mono-lower alkylamino group, and di-lower alkylamino group,or five- to six-membered heteroaryl group selected from the groupconsisting of pyrimidinyl, pyridinyl, thienyl, thiazolyl,1,3-benzodioxanyl and furyl, wherein said heteroaryl group isunsubstituted or substituted with one to four identical or differentsubstituents selected from the group consisting of lower alkyl group,lower alkoxy group, lower alkoxycarbonyl group, carboxyl group, halogenatom, nitro group, cyano group, amino group, mono-lower alkylaminogroup, and di-lower alkylamino group, wherein said lower alkyl group isunsubstituted or substituted with one to four identical or differentsubstituents selected from the group consisting of halogen atom, loweralkoxy group, carboxyl group, amino group, mono-lower alkylamino group,and di-lower alkylamino group; R₂ is lower alkyl group, lower alkenylgroup or lower alkynyl group, and R₂ is unsubstituted or substitutedwith one to three identical or different substituents selected from thegroup consisting of hydroxyl group, lower alkoxy group, cycloalkylgroup, halogen atom, carboxyl group and lower alkoxycarbonyl group; R₃is phenyl group which is unsubstituted or substituted with one to fouridentical or different substituents selected from the group consistingof lower alkyl group which is unsubstituted or substituted with one ormore identical or different halogen atoms, lower alkoxy group, halogenatom, lower alkylthio group, lower alkylsulfinyl group, loweralkanesulfonyl group, carboxyl group, lower alkoxycarbonyl group andcarbamoyl group; and R₄ and R₅ are the same or different and each ishydrogen atom or lower alkyl.
 2. The arylethenesulfonamide compound or apharmaceutically acceptable salt thereof according to claim 1 inwhich:Ar is thienyl group or aryl group which is unsubstituted orsubstituted with one to five identical or different substituentsselected from the group consisting of lower alkyl group which isunsubstituted or substituted with one or more identical or differenthalogen atoms, lower alkoxy group, lower alkoxycarbonyl group, carboxylgroup, halogen atom, nitro group and cyano group; X is oxygen atom or agroup represented by a formula --NH--; Y is oxygen atom; R₁ is loweralkyl group which is unsubstituted or substituted with one or moreidentical or different halogen atoms, cycloalkyl group, aryl group whichis unsubstituted or substituted with one to five identical or differentsubstituents selected from the group consisting of lower alkyl groupwhich is unsubstituted or substituted with one or more identical ordifferent halogen atoms, lower alkoxy group, lower alkoxycarbonyl group,carboxyl group, halogen atom, nitro group, cyano group and C₁₋₃alkylenedioxy group, or five- to six-membered heteroaryl group selectedfrom the group consisting of pyrimidinyl, pyridinyl, thienyl, thiazolyl,1,3-benzodioxanyl and furyl, wherein said heteroaryl group isunsubstituted or substituted with one to four identical or differentsubstituents selected from the group consisting of lower alkyl groupwhich is unsubstituted or substituted by one or more identical ordifferent halogen atoms, lower alkoxy group, lower alkoxycarbonyl group,carboxyl group, halogen atom, nitro group and cyano group; and R₃ isphenyl group which is unsubstituted or substituted with one to fouridentical or different substituents selected from the group consistingof lower alkyl group which is unsubstituted or substituted with one ormore identical or different halogen atoms, lower alkoxy group, halogenatom, carboxyl group and lower alkoxycarbonyl group.
 3. Thearylethenesulfonamide compound or a pharmaceutically acceptable saltthereof according to claim 1 in which:Ar is thienyl group, naphthylgroup or phenyl group which is unsubstituted or substituted with one tofive substituents selected from the group consisting of lower alkylgroup which is unsubstituted or substituted by one or more identical ordifferent halogen atoms, lower alkoxy group and halogen atom; R₁ islower alkyl group which is unsubstituted or substituted by one or moreidentical or different halogen atoms; cycloalkyl group, phenyl group isunsubstituted or substituted with one to five substituents selected froma group consisting of lower alkyl group which is unsubstituted orsubstituted by one or more identical or different halogen atoms, loweralkoxy group, nitro group and C₁₋₃ alkylenedioxy group, or five- tosix-membered heteroaryl group selected from the group consisting ofpyrimidinyl, pyridinyl, thienyl, thiazolyl, 1,3-benzodioxanyl and furyl,wherein said heteroaryl group is unsubstituted or substituted with oneto four substituents selected from the group consisting of lower alkylgroup which is unsubstituted or substituted by one or more identical ordifferent halogen atoms, and lower alkoxy group; R₂ is lower alkynylgroup or lower alkyl group which is unsubstituted or substituted withone to three substituents selected from the group consisting of hydroxylgroup, lower alkoxy group, cycloalkyl group and halogen atom; and R₃ isphenyl group which is unsubstituted or substituted with one to foursubstituents selected from the group consisting of lower alkyl group,lower alkoxy group and lower alkoxycarbonyl group.
 4. Thearylethenesulfonamide compound or a pharmaceutically acceptable saltthereof according to claim 1 in whichAr is phenyl group which isunsubstituted or substituted by one or more identical or different loweralkyl groups, or thienyl group; X is oxygen atom; R₁ is phenyl groupwhich is unsubstituted or substituted with lower alkoxy group or five-to six-membered heteroaryl group selected from the group consisting ofpyrimidinyl, pyridinyl, thienyl, thiazolyl, 1,3-benzodioxanyl and furyl,wherein said heteroaryl group is unsubstituted or substituted with oneor more identical or different lower alkyl groups; R₂ is lower alkynylgroup or lower alkyl group which is unsubstituted or substituted withone to three identical or different substituents selected from the groupconsisting of hydroxyl group and halogen atom; and R₃ is phenyl groupwhich is substituted with one or more identical or different loweralkoxy groups.
 5. The arylethenesulfonamide compound or apharmaceutically acceptable salt thereof according to claim 1 in whichAris phenyl group or thienyl group; R₁ is pyrimidinyl group; R₂ is loweralkyl group which is unsubstituted or substituted with one or moreidentical or different halogen atoms; R₃ is phenyl group which issubstituted with one or more identical or different lower alkoxy groups;R₄ is hydrogen atom or lower alkyl group; and R₅ is hydrogen atom. 6.The arylethenesulfonamide compound according to claim 1 which is chosenfrom the following compounds as well as saltsthereof:N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide,N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide,N-[6-(2-fluoroethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide,N-[6-(2-propynyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide,N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-1-methyl-2-phenylethenesulfonamide,N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-1-ethyl-2-phenylethenesulfonamide,andN-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(2-thienyl)ethenesulfonamide.7. A pharmaceutical composition comprising:an arylethenesulfonamidecompound represented by the following formula (I) or a pharmaceuticallyacceptable salt thereof: ##STR21## in which Ar is a thienyl group or anaryl group which is unsubstituted or substituted with one to fiveidentical or different substituents selected from the group consistingof lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group,carboxyl group, halogen atom, nitro group, cyano group, amino group,mono-lower alkylamino group, di-lower alkylamino group, hydroxyl groupand C₁₋₃ alkylenedioxy group, wherein said lower alkyl group isunsubstituted or substituted with one to four identical or differentsubstituents selected from the group consisting of halogen atom, loweralkoxy group, carboxyl group, amino group, mono-lower alkylamino group,and di-lower alkylamino group; X is oxygen atom, sulfur atom or a grouprepresented by --NH--; Y is oxygen atom or sulfur atom; R₁ is hydrogenatom, lower alkyl group which is unsubstituted or substituted with oneor more identical or different halogen atoms, cycloalkyl group, arylgroup which is unsubstituted or substituted with one to five identicalor different substituents selected from the group consisting of loweralkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxylgroup, halogen atom, nitro group, cyano group, amino group, mono-loweralkylamino group, di-lower alkylamino group, hydroxyl group and C₁₋₃alkylenedioxy group, wherein said lower alkyl group is unsubstituted orsubstituted with one to four identical or different substituentsselected from the group consisting of halogen atom, lower alkoxy group,carboxyl group, amino group, mono-lower alkylamino group, and di-loweralkylamino group, or five- to six-membered heteroaryl group selectedfrom the group consisting of pyrimidinyl, pyridinyl, thienyl, thiazolyl,1,3-benzodioxanyl and furyl, wherein said heteroaryl group isunsubstituted or substituted with one to four identical or differentsubstituents selected from the group consisting of lower alkyl group,lower alkoxy group, lower alkoxycarbonyl group, carboxyl group, halogenatom, nitro group, cyano group, amino group, mono-lower alkylaminogroup, and di-lower alkylamino group, wherein said lower alkyl group isunsubstituted or substituted with one to four identical or differentsubstituents selected from the group consisting of halogen atom, loweralkoxy group, carboxyl group, amino group, mono-lower alkylamino group,and di-lower alkylamino group; R₂ is lower alkyl group, lower alkenylgroup or lower alkynyl group where each of which is unsubstituted orsubstituted with one to three identical or different substituentsselected from the group consisting of hydroxyl group, lower alkoxygroup, cycloalkyl group, halogen atom, carboxyl group and loweralkoxycarbonyl group; R₃ is phenyl group which is unsubstituted orsubstituted with one to four identical or different substituentsselected from the group consisting of lower alkyl group which isunsubstituted or substituted with one or more identical or differenthalogen atoms, lower alkoxy group, halogen atom, lower alkylthio group,lower alkylsulfinyl group, lower alkanesulfonyl group, carboxyl group,lower alkoxycarbonyl group and carbamoyl group; and R₄ and R₅ are thesame or different and each is hydrogen atom or lower alkyl; and apharmaceutically acceptable carrier.
 8. A pharmaceutical compositionaccording to claim 7 wherein said compound is an endothelin receptorantagonist.